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COPYRIGHT DEPOSIT. 



THE TREATMENT OF SYPHILIS 



THE MACMILLAN COMPANY 

MEW YORK • BOSTON • CHICAGO • DALLAS 
ATLANTA ■ SAN FRANCISCO 

MACMILLAN & CO., Limited 

LONDON • BOMBAY • CALCUTTA 
MELBOURNE 

THE MACMILLAN CO. OF CANADA, Ltd. 

TORONTO 






m 



THE TREATMENT 
OF SYPHILIS 



BY 
H. SHERIDAN BAKETEL, A.M., M.D. 

FELLOW OF THE AMERICAN COLLEGE OF PHYSICIANS; LT. COLONEL, MEDICAL RESERVE 

CORPS, UNITED STATES ARMY; PROFESSOR OF PREVENTIVE MEDICINE AND HY- 

GD3NE AND LECTURER ON GENTTO- URINARY DISEASES AND SYPHILIS IN THE 

LONG ISLAND COLLEGE HOSPITAL, BROOKLYN; ATTENDING SYPHILOLO- 

GIST AND CHIEF OF CLINICS, VOLUNTEER HOSPITAL, NEW YORK; 

GENITO-URINARY SURGEON TO THE HOUSE OF RELLEF OF THE 

NEW YORK HOSPITAL; MEDICAL DLRECTOR OF THE 

H. A. METZ LABORATORIES; MEMBER OF THE 

AMERICAN UROLOGICAL ASSOCIATION, ETC. 



Nero flark 

THE MACMILLAN COMPANY 

1920 

All nghts reserved 



4>4 



Copyright, 1920 
By THE MACMILLAN COMPANY 



Set up and electrotyped. Published March, 1920. 



.A366015 



TO MY BELOVED FATHER, 
THE REVEREND OLIVER SHERMAN BAKETEL, D.D. 

WHOSE SAINTLY LIFE HAS BEEN AN ABIDING SOURCE OF ADMIRATION, EN- 
COURAGEMENT AND DEVOTION, THIS BOOK IS AFFECTIONATELY DEDICATED 



PREFACE 

To be successful in the treatment of syphilis, the physician 
must be the master of intravenous medication, for resultful 
treatment of lues is dependent to a very great extent on the ad- 
ministration of arsphenamine or neoarsphenamine. 

The existing textbooks covering the field of syphilis, while 
strong in diagnosis and prognosis, are weak in that part of treat- 
ment which concerns the actual introduction of arsenical prod- 
ucts into the system. They advise their employment but fail 
to give the readers in minutiae the various steps by which a suc- 
cessful administration is accomplished. This fact is the raison 
d'etre of this book. 

It is not a volume for the skilled syphilographer, who has a 
technic which is entirely satisfactory to himself, but rather is 
intended for those physicians who have not heretofore employed 
the intravenous method of injection or those whose acquaintance 
therewith is limited. To some the elaborate detail of description 
as to the preparation and injection of salvarsan may appear 
elementary, but in that very fact lies its strength. A wide ex- 
perience in the treatment of lues with the arsenicals and a com- 
prehensive knowledge of this field of medical practice has dem- 
onstrated that many physicians are lacking in information as 
to the "whys, wheres and hows" of intravenous medication. It 
is for this great body of medical men who desire to treat intelli- 
gently and skillfully the luetic cases which come to their atten- 
tion that this book has been written. 

The author has drawn not only upon his own knowledge in its 
preparation but has also consulted the leading authorities on the 
disease. Credit has been given so far as known and we are in- 
debted to many syphilographers and professional friends for 
advice and help. 

Particular gratitude is expressed to Dr. John A. Fordyce and 
to Dr. Henry H. Morton for valuable suggestions and assistance, 



viii PREFACE 

as well as to Dr. Chester N. Myers, U. S. Public Health Service, 
and Dr. A. E. Sherndal for collaboration in the preparation of the 
chemistry of the arsenicals. 

In carrying out the professional work on which the contents 
of this book are based, all brands of arsphenamine and neoar- 
sphenamine have been utilized, including the German, American, 
English and Canadian, but the majority of the cases have been 
treated with salvarsan and neosalvarsan which seem to be the 
counterparts of the original products. 

H. S. B. 
1 6 Fifth Avenue, New York. 



CONTENTS 

CHAPTER I pAGE 

The Part of the Wassermann and Lange's Chloride of Gold 
Tests est the Diagnosis and Control of the Various Forms of 
Luetic Infection i 

CHAPTER II 
Anttluetic Agents 10 

CHAPTER III 
The History and Chemistry of Arsphenamine n 

CHAPTER IV 
The Chemotherapy of Arsenic Compounds 25 

CHAPTER V 
Indications, Contraindications and Efficiency of Arsphenamine 30 

CHAPTER VI 
A Plan for Antiluetic Treatment 37 

CHAPTER VII 
The Technic of Arsphenamine Administration 42 

CHAPTER VIII 
The Technic of Neoarsphenamine Administration 69 

CHAPTER IX 
The Methods of Employing the Mercurials and Iodides 77 

CHAPTER X 

Reactions and Accddents Following the Use of Arsphenamine . . 88 



x CONTENTS 

CHAPTER XI 

PAGE 

The Wassermann Reaction and the Effects of Treatment 
Thereon 105 

CHAPTER XII 
The Treatment of Syphilis of the Central Nervous System. ... 114 

CHAPTER XHI 

The Treatment of Congenital, Malignant and Visceral Syphilis 139 

CHAPTER XIV 
Syphilitic Re-infection 150 

CHAPTER XV 
The Cure of Syphilis 152 



LIST OF ILLUSTRATIONS 

The Intravenous Injection of Arsphenamine: 

The apparatus necessary, for articles on pages 42-43 Facing p. 42 t 

Distilling Apparatus: 

A simple type for physicians who have no gas, electricity 

or running water " "45 r 

Distilling Apparatus: 

A simple and inexpensive water still for physicians who 

have laboratories " " 46 

Apparatus for Holding Normal Sodium Hydroxld Solution " " 49 
The Intravenous Injection of Arsphenamine: 

The patient, by twisting his shirt sleeve with the left hand, 

makes a very satisfactory tourniquet " "52 

The Intravenous Injection of Arsphenamine: 

The introduction of the Fordyce needle into the vein " "54 

The Intravenous Injection of Arsphenamine: 

The needle having been introduced into the vein, etc " "56 

The Intravenous Injection of Neoarsphenamtne " "73 

The Intravenous Injection of Neoarsphenamtne: 

Tourniquet has been removed and the concentrated solu- 
tion is being introduced into the vein, etc " "74 

The Intravenous Injection of Neoarsphenamtne: 

The injection having been satisfactorily completed, etc " "76 

Syringe and Needle for Intramuscular Mercurial In- 
jection " "80 

The Intramuscular Injection of Mercury " "82 

The Intramuscular Injection of Mercury: 

After the area has been sterilized with alcohol or iodin, etc. . " " 84 
The Intramuscular Injection of Mercury: 

After the mercury has been slowly deposited in the mus- 
cles, etc " "86 



/ 
/ 



THE TREATMENT OF SYPHILIS 



THE TREATMENT OF SYPHILIS 



CHAPTER I 

THE PART OF THE WASSERMANN AND LANGE'S CHLORIDE OF GOLD 
TESTS IN THE DIAGNOSIS AND CONTROL OF THE VARIOUS FORMS 
OF LUETIC INFECTION 

The Wassermann Reaction. — It is incomprehensible to think 
of treating a case of syphilis without the frequent utilization of 
the Wassermann test. While this test has been decried by certain 
individuals and while every careful observer will admit that 
it is not an infallible test, it would be out of the question in our 
opinion to treat lues successfully without its employment. 

Throughout the pages of this book we show in the discussion 
of various matters of technic the occasion for employing the 
Wassermann reaction, because so far as we are able to determine 
it is an agent for the perfection of accuracy in diagnosis which is 
without an equal in the light of our present knowledge. Not 
only does it assist us diagnostically, but it also enables us to 
arrive more definitely at a prognosis. 

It would be out of place in a treatise of this sort to go into the 
technic of the Wassermann reactions but, in view of its very 
great importance, it seems advisable to discuss a few of the terms 
that are being used in connection with the Wassermann. Re- 
produced herewith are extracts written by Drs. O. S. Hillman 
and A. M. Burgess for Mallory and Wright's excellent work on 
Pathological Technique. (W. B. Saunders Co., Philadelphia, 
1918.) 

Complement (Alexine). — "This is a substance which is found 
in all fresh sera; its activity is destroyed by exposure to heat at 
55 or 56 C. for half an hour. Serum treated in this way is said 
to be inactivated, and can be reactivated by the addition of 



2 THE TREATMENT OF SYPHILIS 

another serum containing active complement. The sera of 
various animals differ in their complementary activity and also 
in their fLxability, which is another characteristic that is possessed 
by complement. Anti-complementary action is a property which 
develops in a serum on standing or which may be present to a 
certain degree at the time the serum is drawn. In selecting a 
serum for the Wassermann reaction it is best to choose one which 
has the greatest degree of activity and taxability. It has been 
found that guinea-pig serum fulfills these demands probably 
better than the serum of any other species. 

" Amboceptor. — This is a specific reaction product, which 
may be present in any normal serum, and which can be pro- 
duced in the serum of an animal by repeated injections (immuni- 
zation) of cells or substances (erythrocytes, serum, egg-albumin, 
etc.), for which it has no natural amboceptor. Amboceptors 
that are normally present in serum are called natural ambocep- 
tors ; those which are produced as the result of artificial immuniza- 
tion are called immune amboceptors. Amboceptors are classi- 
fied according to the particular substances employed in their 
production; for example, hemolytic amboceptors (also called 
hemolysins) are those that are produced by the injection of red 
blood-corpuscles into an animal; bacteriolytic amboceptors 
(bacteriolysins) are produced by the injection of bacterial ex- 
tracts. An amboceptor is specifically defined by prefixing the 
term ' anti ' to the name of the particular species employed in its 
production; for instance, when sheep's erythrocytes are the 
immunizing agent, the amboceptor is designated as an anti- 
sheep hemolytic amboceptor. 

"Complement and amboceptor are the two factors necessary 
in the production of serum hemolysis. This can be demon- 
strated by a simple experiment, as follows: immunize a rabbit to 
human red blood-corpuscles by means of repeated injections, 
thereby producing in the rabbit serum an anti-human hemolytic 
amboceptor. If serum from such a rabbit is brought into con- 
tact with a suspension of washed human red blood-corpuscles, 
dissolution of the corpuscles or hemolysis will take place; if, how- 
ever, the rabbit serum be heated to 56 C. for one-half hour (in- 



WASSERMANN AND LANGE'S TESTS 3 

activated), and then corpuscles added, no hemolysis will occur. 
Finally, if normal human serum or normal guinea-pig serum be 
added to the mixture, hemolysis will go on as before. These 
three factors which enter into this reaction, namely, the com- 
plement, the hemolytic amboceptor, and the red blood-corpus- 
cles, constitute what is called, for the sake of brevity, the hemo- 
lytic system. 

"The function of the amboceptor in the above reaction of 
hemolysis is to sensitize or prepare the erythrocytes for the action 
of the complement; the latter than has the power of causing 
dissolution of the red cells, resulting in a clear red fluid. Neither 
amboceptor nor complement acting alone can produce this re- 
sult. For complete hemolysis a definite ratio must exist be- 
tween the various factors — amboceptor, complement, and ery- 
throcytes. The requisite strength and proportion of these three 
can readily be estimated by titration. 

11 Antigens and Antibodies. — Antigens are substances which, 
when injected into a suitable animal, are capable of producing 
in that animal substances called antibodies, the latter thus being 
specific reaction products. Erythrocytes, bacteria, and pro- 
teins are examples of antigens. Under antibodies are included 
hemolytic and bacteriolytic amboceptors, agglutinins, and pre- 
cipitins. Antibodies are also found in the serum of patients 
suffering from infections with microorganisms. In typhoid 
fever, for instance, an antibody is developed in the patient's 
serum as a result of the action of the typhoid bacillus upon the 
immunizing mechanism of the body. 

" Generally speaking, it may be stated that antigens and anti- 
bodies bear a specific relationship toward one another; for in- 
stance, the hemolytic amboceptor produced by injecting a rabbit 
with sheep's red blood-corpuscles acts with these corpuscles only 
and with no others. The agglutination of typhoid bacilli by the 
serum of the typhoid patient is also an example of this intimate 
connection between antigen and antibody; this fact is made 
practical use of in the Widal reaction for the determination of 
the typhoid agglutinin (antibody) . The phenomenon of precipi- 
tation is another instance of the visible and direct action between 



4 THE TREATMENT OF SYPHILIS 

antigen and antibody. Both agglutination and precipitation 
are dual mechanisms requiring no intermediate agent to com- 
plete the reaction. 

"In syphilis an antibody is supposed to be developed in the 
patient's serum, probably through the action of the treponema 
pallidum. It seems to be doubtful, so far as we know at present, 
whether the antibody in syphilis is actually specific or not. How- 
ever, from a practical standpoint it may be said that it is the 
presence or absence of this so-called syphilitic antibody that we 
seek to demonstrate in the serum diagnosis of the disease. 

" Complement Fixation. — As stated above, antigen and anti- 
body unite with one another specifically, and, when united, ac- 
quire the property of fixing or absorbing complement. This 
fact can be best illustrated by the interaction of two sets of 
antigen-antibody combination. Take, for example, a suspension 
of typhoid bacilli (antigen) and bring it into contact with typhoid 
serum (antibody) ; if complement is now added, bacteriolysis will 
result. That complement has been fixed or absorbed by this 
antigen-antibody combination is evidenced by the fact that if 
red blood-corpuscles and their specific amboceptor (another 
antigen-antibody combination) be added later, no hemolysis 
will occur; complement, in other words, is not available for 
hemolysis on account of being fixed by the first antigen-antibody 
combination. This is the well-known phenomenon of comple- 
ment fixation or deviation of Bordet and Gengou, upon which 
the Wassermann reaction and its various modifications are based. 
The so-called syphilitic antibody present in a patient's serum 
when brought into contact with an antigen is capable of fixing 
complement. This reaction is indicated by absence of hemolysis 
when the other two factors of the hemolytic system are 
added. 

"When the reaction was first introduced, it was thought that 
the antigen used in the diagnosis of syphilis was specific, as it 
was then made from the liver of a syphilitic fetus. This was the 
nearest approach obtainable to actual extracts of the causative 
agent, namely, treponema pallidum. It has been conclusively 
proved that this original antigen is not specific, as it has been 



WASSERMANN AND LANGE'S TESTS 5 

found that extracts of normal livers, as well as other organs, and 
also certain lecithin preparations will fix complement in contact 
with not only luetic sera but also sera from patients infected 
with leprosy, yaws, sleeping-sickness, and malaria. The variabil- 
ity in the statistics of different writers is probably due to the 
variety of antigens employed, and at present this appears to be 
the principal limitation to the specificity of the reaction. 

"The aqueous extract of the liver of a syphilitic fetus, which is 
used as an antigen in the original Wassermann reaction, is not 
employed in the following methods on account of its instability, 
and, incidentally, on account of the frequent difficulty of ob- 
taining syphilitic fetuses. The modifications of the original 
test which have been devised depend, for the most part, on varia- 
tions in the source of the antigen and in the employment of a 
different hemolytic system. 

" Probably the most important modification is that of Noguchi, 
in which an antihuman hemolytic system is substituted for the 
antisheep and the acetone-insoluble fraction of an alcoholic 
extract of a normal organ (heart, liver, or kidney) is used as 
antigen. Plain alcoholic extracts of normal organs and of livers 
and spleens of syphilitic fetuses have been used by many workers 
in the Wassermann reaction, but at the present time the best 
antigen seems to be an alcoholic extract of human heart muscle 
saturated with cholesterin. On account of its stability for long 
periods, this antigen is particularly valuable, especially when 
reactions are done at infrequent intervals. 

"For purposes of distinction the two following methods will be 
designated as the Wassermann and Noguchi reactions respec- 
tively, although, strictly speaking, the name Wassermann should 
be applied to the original method of doing the reaction — that 
is, with the aqueous extract of a liver of a syphilitic fetus. 

"In the Wassermann reaction the patient's serum is inacti- 
vated in order to destroy the native complement, which is pres- 
ent, as a rule, in an appreciable amount. Complement of known 
strength necessary for the reaction is supplied by fresh guinea- 
pig serum. In the Noguchi reaction an antihuman hemolytic 
system is employed, as Noguchi maintains that, owing to the 



6 THE TREATMENT OF SYPHILIS 

presence in human serum of varying amounts of natural am- 
boceptor for sheep's corpuscles, many positive reactions are 
rendered negative in the Wassermann test on account of an in- 
crease in the total amount of amboceptor present, thus disturbing 
the proper proportion between amboceptor and complement 
necessary for complete fixation. It is not necessary to inactivate 
the patient's serum in the Noguchi reaction, as the human com- 
plement is only very slightly hemolytic for corpuscles of the same 
species, and also because the amount of complement present is 
practically negligible, owing to the small quantity of patient's 
serum used for the test." 

Dr. Archibald McNeil, director of laboratories of the National 
Pathological Laboratories, differs from the statement above 
that cholesterinated antigen is the best and most reliable one to 
employ. Such an antigen may at times give positive results in 
cases free from luetic infection, and, for this reason, Dr. McNeil 
believes that the plain alcoholic antigen is much safer and gives 
results that coincide more closely with clinical findings than does 
the cholesterinated antigen. The latter undoubtedly gives 
positive results in a number of latent and treated cases of lues 
in which the plain alcoholic extract antigen gives negative re- 
sults. Dr. McNeil feels it would be better to obtain negative re- 
sults in a positive case of lues than positive results in negative 
cases, especially as it is generally understood by the medical 
profession that a negative result does not exclude the possibility 
of luetic infection. 

Very few practitioners are qualified by experience to make the 
Wassermann test, and those who are interested in it and desire 
the exact technic are referred to Mallory and Wright's book. 

Lange's Colloidal Gold Test 

They will find therein also a good description of Lange's col- 
loidal gold test of the cerebrospinal fluid in syphilis. This test is 
easily and quickly made. "It consists, " says Dr. John A. Fordyce 
(Am. Jour. Med. Sci., October, 1916) " of a series of color changes 
which occur so characteristically and constantly that they may 



WASSERMANN AND LANGE'S TESTS 7 

be said to be specific. It is performed with ten dilutions of spinal 
fluid in geometrical progression from i to 10 to i to 5120. The 
color change depends on the amount of colloidal gold precipi- 
tated and varies from the negative salmon red through red blue, 
lilac or blue, blue gray or gray, and colorless. These changes 
may be plotted in curves or are arbitrarily expressed from zero 
to five. A negative colloidal gold would show no change and 
would therefore be expressed as 0000000000. In tabes and cere- 
brospinal syphilis the reaction occurs in the lower dilutions with 
the intensity of the change in the third and fourth or fourth and 
fifth tubes. The term ' luetic zone' or 'luetic curve' is used 
to describe this reaction. The reading would be as follows: 
1 133 200000 or 1223320000. In meningitis of non-syphilitic 
origin the maximum change occurs beyond the syphilitic zone — 
that is, in the higher dilutions — while in paresis precipitation of 
the colloidal gold occurs regularly in the first four to eight tubes 
with decolorization or a turbidity, and the reading represented 
as 5555431000 or as many fives as there are decolorized tubes. 
To this zonal change Miller and Levy applied the term ' paretic 
curve.' A properly standardized — that is, a neutral solution of 
colloidal gold — shows either no change at all with a normal 
spinal fluid or produces a slight variation with a bluish nuance 
in the first four or five tubes which is negligible. Some cases 
may even give a change to a frank red blue in the first four tubes, 
so that the reading would be 1111000000, but with all the other 
laboratory findings negative it has been shown this had no 
diagnostic import. 

"It may be said," continues Fordyce, " that, as a rule, there is 
a parallelism between the other positive findings in the fluid and 
a positive gold reaction. The significance of any one of the in- 
dividual abnormalities must be appreciated before a proper in- 
terpretation can be placed upon the laboratory findings. We 
know that a lymphocytosis alone is not pathognomonic of syphilis 
as a mild grade is met with in other affections of the central 
nervous system and that the cell count cannot be relied upon to 
differentiate between tabes, cerebrospinal syphilis, and general 
paresis, as an equally high pleocytosis may be met with in any of 



8 THE TREATMENT OF SYPHILIS 

these conditions. So too the presence of globulin alone indicates 
organic disease of the brain or cord, but does not separate 
syphilitic from non-syphilitic disease. 

" More positive information is derived from the complement- 
fixation test, as a positive Wassermann occurs only in lues. How- 
ever, his test by itself does not supply a differential diagnosis 
as fixation to 0.2 c. c. or lower is met with not only, in paresis but 
in some cases of progressive tabes and cerebrospinal syphilis. 
On the other hand, with a distinctly syphilitic process, as in 
cerebral endarteritis, abortive or stationary forms of tabes, and 
some types of cerebrospinal syphilis, the Wassermann may be 
completely negative. In the last-named cases a supplementary 
gold test is of value in demonstrating the luetic nature of the 
condition. Its greatest value and by far most prominent role, 
however, is in distinguishing between paresis and the conditions 
which simulate it as well as its prognostic significance in tabetics 
who show no mental impairment but give a paretic curve. Since 
the application of the gold sol test a number of patients in whom 
no cerebral involvement was suspected have given the curve 
characteristic of paresis." 

Clinical Application of the Wassermann Reaction 

This subject is so succinctly set forth by Dr. Henry H. Morton 
of Brooklyn in his admirable book (Genito-Urinary Diseases 6" 
Syphilis, p. 739, 1918, C. V. Mosby Co., St. Louis), that it is 
presented here in toto: 

"The diagnostic value of the Wassermann test depends upon 
the fact that the antibody contained in the serum causing the 
reaction is specific, occurring only in the serum of luetics. Ex- 
cept in rare instances this has been found to be true. Positive 
reactions have been obtained in frambesia, relapsing fever, 
trypanosome infections, and tubercular leprosy. It is also found 
positive after veronal, morphin, scopolamin, ether narcosis 
(Wolfsohn), and frequently in sera obtained just before or after 
death. Therefore, while it is true that a positive reaction is ob- 
tained in a few diseases and conditions other than syphilis, the 



WASSERMANN AND LANGE'S TESTS 9 

differential diagnosis between syphilis and those diseases should 
not be difficult, at least in this country, and the reaction may be 
said to be practically specific. 

"A negative reaction, on the other hand, can not be accepted 
as proof that the disease does not exist, as negative findings have 
been obtained in a small percentage of active cases of syphilis. 
If, however, a negative reaction is repeatedly obtained after 
several trials made at intervals, it is almost positive proof that 
the disease is not present. The reaction appears from two to 
four weeks after the appearance of the initial lesion, and persists 
throughout all stages of the disease unless influenced by treat- 
ment. A positive reaction has been obtained forty or fifty years 
after infection. Quite often a positive reaction may be obtained 
before the appearance of secondary symptoms. In the active 
stages of the disease 95 per cent of cases give a positive Wasser- 
mann reaction and at least 75 per cent of tertiary cases. 

" In latent cases of the disease, while the continued existence 
of the spirochetal renders the patients liable to outbreaks of 
symptoms at any time, nevertheless, the organism is often in a 
dormant state, which makes the appearance of symptoms less 
likely. In these latent cases a positive reaction is obtained in 
50 per cent of the cases. It is in this class of cases that the Was- 
sermann reaction is of special value as these patients are often 
apparently healthy and may give no history of ever having had 
the disease. Oftentimes a negative reaction in these latent cases 
may be transformed into a positive reaction by the administra- 
tion of a short course of mercury or salvarsan." 



CHAPTER II 



ANTI LUETIC AGENTS 



In the constitutional treatment of syphilis dependence is 
placed mainly on three drugs, arsenic, mercury, and iodin in 
the form of the" iodides. The preparations mostly used are: 



Arsenic 



Mercury 



Iodides 



Given by 
Intravenous, or 
Intramuscular, or 
Subcutaneous 


Arsphenamine 
Neoarsphenamine 


Injection or by rectum 


j 




Protiodid 


• 


Bichlorid 


Given 
orally 


Mercury with chalk 

Biniodid 

Calomel 




Blue Mass 


By 

Fumigation 

or 

Inhalation 


Calomel 


• 


By 

Inunction 


Oleate — 10 per cent 
Unguentum hydrargyri 


By 

Hypodermic 
Injection in 
Gluteal 


Soluble 


Bichlorid 
Succinimid 
Biniodid 
Benzoate 


Muscles 


Insoluble 


Salicylate 
Calomel 






Gray oil 


Given 


Potassium iodid 


By Hypodermic Injection 
By Enema or 
Intravenously 


Sodium iodid 

Ammonium i< 

„ Strontium ioc 


3did 

lid 



CHAPTER III 

THE HISTORY AND CHEMISTRY OF ARSPHENAMINE 

Before the knowledge of chemotherapy had reached its present 
stage, arsenic compounds had been used haphazardly for the 
cure or alleviation of syphilis and other protozoal diseases for i 
many years, probably just as long as mercury. At first only 
inorganic arsenic derivatives were known, but with the exten- 
sion in the field of preparative organic chemistry which occurred 
early in the 19th century, some organic combinations of arsenic 
became known which were used to some extent in therapy. The 
recent development in the use of arsenic compounds in medicine 
received its original impetus in the discovery of the curative 
action of atoxyl 1 on sleeping-sickness. The chemical struc- 
ture of this substance, which was obtained by the action of 
arsenic acid on aniline, was first correctly explained in 1907, 
when Ehrlich demonstrated that it was the sodium salt of 
para-amido-phenyl arsinic acid. 2 The possibility of subject- 
ing this substance to the chemical transformations character- 
istic of benzol derivatives was thus opened, and from then 
on attention was chiefly centered on such aromatic organic 
arsenic derivatives because of their comparatively low toxicity 
and apparent curative properties. In addition to atoxyl, "Hec- 
tine," a benzene sulfonate of atoxyl, 3 

NaO\ 



O = A < ) -NH- S0 2 C6H £ 

HO/ 



"Arsacetin," an acetyl atoxyl, 4 
NaO\ 



O = As < > -NHCOCH 3 

HO/ 

and "Asiphyl," a mercury salt, 5 

[NH 2 • C 6 H 4 • AsO(OH) .0] 2 Hg 

were proposed as therapeutic agents. 



12 THE TREATMENT OF SYPHILIS 

Affinity between Certain Living Cells and Chemical Sub- 
stances. — The haphazard method of using these compounds 
stopped with the development of a definite theory of specific 
affinity between certain living cells and certain chemical sub- 
stances, and its practical application to internal antisepsis for 
the cure of trypanosome and spirochetal diseases. Binz and 
Schulz 6 had found that arsenic acid was reduced in animal 
tissues to arsenious acid. It had also been noted that cacodylic 
acid was reduced in the organism. Ehrlich concluded from this 
that the arsenic compounds which had been used hitherto, and 
which were all derivatives of pentavalent arsenic, did not exercise 
an action on the parasites until after they had been reduced by 
the organism to the trivalent form. 

Investigation along this line led to the greatest advance 
in the preparation of therapeutically valuable substances. It 
was found that by reducing the pentavalent compounds of 
arsenic to the trivalent form an enormous increase in the power 
to destroy the parasites which cause disease was developed. 
For example, para-oxy-phenyl arsinic acid does not kill try- 
panosomes in dilutions as strong as i or 2%, whereas if reduced 
to the corresponding trivalent arsenic compound, para-oxy- 
phenylarsenoxide, it kills trypanosomes quickly in dilutions of 
1 to 10 million. 7 

Further investigation led Ehrlich to conclusions in regard to 
the mechanism of the action of these drugs on the parasites, 
which form the basis of the theory of arsenic chemotherapy as 
at present generally accepted. According to this theory the 
parasite possesses certain points of attack, termed by Ehrlich 
" chemoceptors " which have a specific affinity for certain chem- 
ical groups, of which trivalent arsenic is one. Other groups, such 
as the amido (NH 2 ), the hydroxyl (OH), appear to anchor them- 
selves to definite parasites and so exert on them the specific 
drug action. 

The Discovery of Salvarsan 

By a combination of work in chemical synthesis and biological 
examination along the lines of this theory, covering many years, 



HISTORY AND CHEMISTRY OF ARSPHENAMINE 13 

Ehrlich and his co-workers arrived at a substance which has pro- 
duced very remarkable therapeutic results. It was originally im- 
ported under the name "Salvarsan" and its manufacture in this 
country by Federal license under the name " Arsphenamine" has 
become an important factor in the industry of synthetic drugs. 
Several million ampules of arsphenamine and its compounds 
have been manufactured and distributed in this country, and 
the Government's campaign against venereal disease in which 
arsenicals of this type will play an important part, has still 
further increased the necessity of production on a large scale. 

In the work which led to the preparation of salvarsan, the 
object sought after was a substance which would combine 
maximum toxicity to the disease-producing parasite with min- 
imum toxicity to the organism which harbored the parasite. 
The measure of the former is the curative dose, of the latter the 
tolerated dose. The success in attaining this object may be 
judged by a comparison of the ratio of curative to tolerated dose 
in some of the better known arsenicals: atoxyl 1 :2, arsacetin 1 13, 
arsenophenyglycine 1:2, salvarsan i:58. 8 

Preparation of Arsphenamine 

The preparation of arsphenamine involves a number of chem- 
ical processes in a field which is comparatively complicated and 
requires a large amount of special knowledge. It is further 
complicated by the necessity of extra precautions on account of 
the great susceptibility of the final product to chemical and 
physical influences. A great variety of methods for its produc- 
tion have been proposed but as might be expected the number 
of processes used for practical purposes is comparatively limited. 

The first step in the synthesis of the aromatic organic arsenic 
compounds is the introduction of arsenic into the benzene nu- 
cleus. The methods which have been applied commercially for 
this purpose are probably limited to three. 

1. The Bechamp condensation, melting arsenic acid with 
aniline to produce arsanilic acid, 9 or with phenol to produce 
para-oxy-phenyl arsinic acid. 10 The best yields are obtained 



14 THE TREATMENT OF SYPHILIS 

in the aniline melt. The process must be carefully regulated as 
to proportions of reagents and temperature, in order to obtain 
the best results. With high temperatures and an excess of 
aniline, the tendency to the formation of secondary arsanilic 
acid is increased. 

With phenol the condensation appears to give less satisfactory 
yields, although as a step in the preparation of arsphenamine it 
has the advantage of leading more directly to the goal. 

2. The arseniation of dimethylaniline with arsenic trichloride, 
leading to N-dimethyl arsanilic acid. This process appears to 
be used in connection with French patents for the manufacture 
of arsphenamine. 11 

3. Bart's reaction, coupling diazo compounds in alkaline 
solution with sodium arsenite. This method is capable of very 
wide application and starting from para-amido-acetanilide has 
been applied commercially to the production of arsanilic acid. 12 
From the arsinic acids produced by these methods a large number 
of derivatives can be obtained, by the usual chemical reactions 
on benzene compounds. The practical production on a large 
scale of some of these requires considerable elaboration. 

The Immediate Mother Substance of Arsphenamine 

The immediate mother substance of arsphenamine is 3-nitro- 
4-hydroxy-phenylarsinic acid. A large number of procedures for 
the preparation of this substance have been proposed. One of 
the methods generally used starts from parahydroxy-phenyl 
arsinic acid, obtained by the action of arsenic acid on phenol, 
or by the diazotization and hydrolysis of arsanilic acid. This 
hydroxy acid is then nitrated at a low temperature to form the 
nitrohydroxy acid. Another method consists in combining ar- 
sanilic with oxalic acid, nitrating the resulting oxalyl compound, 
subsequent saponification and hydrolysis with strong caustic 
potash leading to the nitro-hydroxy acid which is used for con- 
version into arsphenamine. 

The 3-nitro-4-hydroxy-phenyl arsinic acid used for the produc- 
tion of arsphenamine can and should be prepared in a high state 



HISTORY AND CHEMISTRY OF ARSPHENAMINE 15 

of purity. Arsphenamine itself cannot be purified, consequently 
all possible extraneous material should be eliminated, previous 
to the final step in the manufacture. 

From 3-nitro-4-hydroxy-phenyl arsinic acid, the process of pre- 
paring arsphenamine consists in a reduction of the nitro to an 
amino group and a partial reduction of the arsenic acid group, 
forming a double bond between two molecules. The resulting 
insoluble arseno base is then isolated, converted into its soluble 
dihydrochloride, isolated by suitable precipitation, dried thor- 
oughly in a high vacuum, and packed in ampules in vacuum or 
inert gas. 

If the reduction is carried too far, highly toxic arsines may 
be formed, if the reduction is insufficient or improperly carried 
out, the nitro group may be left intact, or the arsenoxides formed. 
Several methods for the reduction and subsequent treatment 
have been proposed. The original scheme was a progressive 
reduction, first of the nitro group by means of sodium amalgam, 
then of the arsenic group by the action of sulfur dioxid in acid 
solution with potassium iodid as a catalyst. 13 Kahn patented 
a procedure involving a complete reduction to the primary 
arsine, which was then added to a solution of the amino-phenyl- 
arsenoxid with which it combined forming the arseno base. 14 
The reduction by means of phosphorous or hypophosphorous 
acid has also been described 15 and the use of zinc dust, zinc 
chlorid and sulfurous acid has been subject of patents. 16 

For the practical purpose of large-scale production sodium 
hydrosulfite has probably been used exclusively, and under 
proper conditions has proven an ideal reagent, although it 
introduces the necessity of removing certain impurities from the 
crude arseno base. When this method is used the reduction takes 
place in one stage, and the arseno base, being insoluble in the 
medium, can be filtered directly. 

For the preparation of the dihydrochlorid, a method has been 
patented for the precipitation of a solution from hydrochloric 
acid. 17 The generally used procedure consists in dissolving the 
base in methyl-alcoholic hydrochloric acid and precipitation of 
the dihydrochloride by means of ether. 18 



16 THE TREATMENT OF SYPHILIS 

In the final steps of the manufacture of arsphenamine it is 
important to exclude atmospheric oxygen. In the reduction by 
sodium hydrosulfite, this is taken care of by the sulfur-dioxid 
formed by the oxidation of the hydrosulfite. During the filtra- 
tion of the base, the preparation of the dihydrochlorid and its 
final isolation, air should be replaced by carbon dioxid or other 
inert gas. To insure a product of maximum stability, it must be 
carefully dried in high vacuum, and all subsequent operations 
conducted in an atmosphere of inert gas. 

There appears to be some doubt as to whether such careful 
precautions are really necessary and it is possible that a pure 
arsphenamine, particularly after moisture and solvents have 
been removed, is a very much more stable substance than ap- 
pears from some of the literature on the subject. There is no 
doubt, however, that in view of the nature of the material and 
the use to which it is put, the best method of procedure is to 
adopt every possible precaution in the manufacture, even at 
the risk of overdoing it. 

Explanatory Diagrammatic Outline 

The large number of proposed chemical procedures for the 
preparation of arsphenamine and its intermediates is outlined in 
the following charts, which show the chemical relationship of the 
various substances to the final product, arsphenamine. 



o : 



?o f i 






~<y 



,1 



•*0 






OmOh 



*0*K> 



0=! 



r** * = 



-fO'fl 



o«i 



!04 



k^I cxoioj 



o*i 



? 




'Oi 



§4 



HISTORY AND CHEMISTRY OF ARSPHENAMINE 19 

It would appear that every conceivable avenue of approach 
has been utilized for the preparation of arsphenamine. It is 
probable, however that only a few of these proposed methods 
have been applied to practical production of the material. The 
value of any single method can only be judged by extensive 
study and application to the production of material which is 
satisfactory chemically, therapeutically and economically. 

The considerable physical and chemical variations in different 
brands of arsphenamine as now obtainable, indicate that the 
processes used by different manufacturers vary to some extent 
either in principle or method of manipulation. Color and solubil- 
ity in solvents, particularly in methyl alcohol, and the ease with 
which the material forms aqueous solutions differ decidedly with 
different brands. The arsenic content varies from about 29 to 
about 33 per cent. Since the theoretical arsenic content of pure 
arsphenamine is 34.2 per cent, these figures represent great 
variations in purity and may affect the dosages used in biological 
tests and clinical practice by as much as 10 per cent. The im- 
purities which produce this low arsenic content as far as at present 
known consist of moisture, various amounts of solvents, inorganic 
material, and sulfur. These variations in the product no doubt 
have an important bearing on variations in clinical results and 
the advantages of standardizing the preparation are obvious. 

The Manufacture of Arsphenamine 

At the present time most American manufacturers produce 
arsphenamine in comparatively small batches, of 500 or 1,000 
grams, and a recently published English monograph on organic 
arsenicals notes with apparent satisfaction that batches of 1,500 
grams are being produced. For quantity production this small 
scale involves the employment of many assistants, working in 
shifts, and an obvious possibility of insufficient control resulting 
in a lack of uniformity in the product. By calling to aid the 
mechanical means well known to the chemical engineer, so as to 
insure absolute and constant control throughout the process, it 
has been found possible to produce salvarsan in batches of over 



20 THE TREATMENT OF SYPHILIS 

7,000 ampules at a time. Careful comparisons have shown that 
the material manufactured on this scale is as good or better than 
can be obtained from small laboratory batches in which identical 
raw materials are used. The capacity of a plant operating on 
this basis is about 14,000 ampules of 0.6 gram every 14 to 16 
hours. This large-scale production also has the advantage of 
insuring the absolute identity of a large amount of material, 
from which data can be obtained in regard to the influence of 
technic and personal factors on the results obtained from the 
administration. At the same time it gives the practitioner 
complete assurance as to the uniformity of a product should he 
desire to use many doses of one batch on a series of patients for 
purposes of comparative study. The product is uniform chem- 
ically, toxicologically and therapeutically. It is identical in 
every respect with the original preparation upon which the 
therapeutic reputation of the drug was established. It is tol- 
erated by test animals in doses of 120 mg. and higher pro kilo 
body weight which represents a very low toxicity as compared 
with other drugs used in a similar manner. 

A criticism of arsphenamine may be made on the ground of 
inconvenience in administration. The product occurs in the 
form of its dihydrochloride, which should be readily soluble in 
water of ordinary temperature. This solution is not suitable for 
injection, however, until the hydrochloric acid has been neu- 
tralized and the arsphenamine then further converted into its 
di-sodium salt. The addition of the improper amount of alkali 
for this purpose, either too much or too little, produces solutions 
which may give trouble in injection. If the arsphenamine 
requires hot or boiling water to form the solution, the preliminary 
preparation of the intravenous solution becomes still more com- 
plicated, and more possibilities of affecting the proper action of 
the drug are introduced. 

The Evolution of Neoarsphenamine 

With the idea of simplifying the technic of administration, 
modifications prepared from arsphenamine have been intro- 
duced which dissolve readily in water, forming solutions which 



HISTORY AND CHEMISTRY OF ARSPHENAMINE 21 

are ready for injection without further manipulation. Of these, 
neoarsphenamine is coming largely into favor, since in addition 
to its convenient administration it is also less toxic than arsphen- 
amine. This substance is prepared from arsphenamine by com- 
bination with sodium formaldehyde sulfoxylate. It occurs in the 
form of its yellow sodium salt, readily soluble in water with 
slightly alkaline reaction. This product is being manufactured 
on a large scale in the United States and a very extended use in 
clinical practice has given satisfactory results. 

The dry sodium salt of arsphenamine has also been proposed 
as a more convenient form for administration. This dissolves 
readily in water forming a solution which corresponds exactly to 
that obtained in the preparation of a properly alkalinized ar- 
sphenamine solution. It has been manufactured in this country, 
but does not appear to have come into any extended use. 

A number of other arsenicals have been proposed as substitutes 
for or as improvements on arsphenamine. Since arsphenamine 
is a patented product and can only be manufactured under 
license, it is obvious that many attempts to introduce competitive 
products will be made. So far, no other arsenical has shown 
advantages which would enable it to replace or compete with 
arsphenamine to any marked degree. 

The Precursors of Arsphenamine 

During the work which culminated in the preparation of ars- 
phenamine, a very large number of other arsenicals were syn- 
thesized and studied, some of which were for a time used in 
therapy. They may be considered as the precursors of arsphe- 
namine, and the results of their use indicated the lines along 
which improvements might be effected. As already noted, 
atoxyl was the first of the extensively used aromatic organic 
arsenicals. This was replaced later by its acetic acid derivative 
under the name of arsacetine. 

After Ehrlich took up the study of these arsenicals and dis- 
covered the decided increase in trypanocidal efficiency caused by 
their reduction to the trivalent arseno compounds, phenyl- 



22 THE TREATMENT OF SYPHILIS 

glycine-arsinic acid was introduced as No. 418 in his experi- 
mental series. Its sodium salt, under the name "spirarsyl" con- 
stituted an important advance over atoxyl and its immediate 
derivatives, and was the most successful remedy among the 
arsenicals which preceded salvarsan. 

It was later replaced by salvarsan, No. 606, of Ehrlich's series, 
which represents the culminating point of this line of research. 
Attempts to simplify its use in therapeutics led to the introduc- 
tion of neosalvarsan and salvarsan sodium which have already 
been described. The former is numbered 914 in Ehrlich's series. 

Working along the same line and with a similar object in view, 
Mouneyrat prepared a phosphamic acid derivative of arsphen- 
amine which was marketed under the name "Galyl" No. 11 16, 
and subsequently a complex disulfonamide of arsphenamine 
appeared under the name "Ludyl," No. 1151 of Mouneyrat's 
series. These preparations both belong to the neoarsphena- 
mine type of arsphenamine derivatives, intended to produce 
neutral or feebly alkaline solutions ready for injection without 
preliminary manipulation. 

Other Arsphenamine Derivatives 

Another type of arsphenamine derivatives which have received 
considerable attention are the co-ordination compounds with 
various metals. This interaction, discovered during Ehrlich's 
researches on salvarsan, appears to be a general one with organic 
arsenical compounds, although on account of their therapeutic 
importance it is chiefly the co-ordination compounds of arsphena- 
mine which have been studied. 

Danysz prepared co-ordination compounds of arsphenamine 
with silver salts, and introduced "Luargol" in which the action 
of the drug is reinforced by silver bromide and antimony oxide. 
A large number of other co-ordination compounds of arsphena- 
mine and neoarsphenamine have been studied, in which salts 
of mercury, silver, gold, copper and platinum are in combination, 
but the preparations mentioned above are the only ones which 
have been used therapeutically to any extent. The same applies 



HISTORY AND CHEMISTRY OF ARSPHENAMINE 23 

to other modifications of the molecule, in which the various char- 
acteristic groups have been substituted or rearranged with a view 
to modifying or improving the therapeutic action. 

It is not many years ago that the chemistry of the organic 
arsenic compounds occupied only a very modest place in chemical 
literature, but in recent years, the interest in their therapeutic 
application has developed a voluminous record of research and 
experiment along these lines, and several monographs on or- 
ganic arsenicals have been published. The chemical structure of 
the arsenicals mentioned above is shown in the following cut, 
and also some of the modifications of arsphenamine which have 
been patented with the object of introduction as arsphenamine 
substitutes. They will indicate some of the lines along which 
attempts are being made to improve or replace the products 
which are now in use. 

Spirarsyl — sodium arsenophenylglycinate 

No. 418 in Ehrich's series 

NHCH 2 COONa NHCH 2 COONa 

I I 

C 6 H 4 — As = As — C 6 H 4 

Galyl — dihydroxy-arsenobenzene-phosphamic acid 

No. 1 1 16 of Mouneyrat's series 

HO.CeHa-As = As-C 6 H 3 .OH 

I I 

P.O(OH) 
Ludyl — benzene-disulphamino-bis-amino-dihydroxy arseno benzene 

No. 1 1 51 of Mouneyrat's series 

/S0 2 NH C 6 H 3 (OH)— As = As— C 6 H 3 (OH)(NH 2 ) 
CeH4 \ S0 2 NH C 6 H 3 (OH)— As = As— C 6 H 3 (0H) (NH 2 ) 



24 THE TREATMENT OF SYPHILIS 

Luargol. — diamino-dihydroxy arseno benzene-silver-bromide-antimonyl- 
sulfate. 

No. 102 of Danysz series 
[(NH 2 )(OH)C6H 3 — As = As— C6H 3 (OH)(NH 2 )]2 Ag Br. SbO. (H 2 S0 4 ) 2 

Typical co-ordination compound; AS Me X 

Me denotes metal || 

X " halogen AS Me X 

BIBLIOGRAPHY 

i. Thomas and Breinl, about 1902. 

2. Ehrlich and Bertheim, Ber. (1907) 40-3292. 

3. Balzer and Mouneyrat, Progres Medical (1909, No. 27); French Patent 

401586 (1908). 

4. U. S. P. 907016 (1908). 

5. May, Baker and Bates, Eng. Pat. 8959 and 24428 (1908) ; Fr. Pat. 
396192; D. R. P. 237787. 

6. Ber. 12, 2200; 14, 2400. 

7. Ber. 42, 28. 

8. Ehrlich and Hata, Experimental Chemotherapy of Spirilloses, London 

1911. 

9. O. and K. Adler, Ber. 41, 932 (1908); Kober, J. A. C. S. (1919) 451. 

10. Mouneyrat, Eng. Pat. 3087 (1908). 
Conant, J. A. C. S. (1919) 431. 

11. Poulenc and Oechslin, Fr. Pat. 449373, 451078, 474056. 

12. Bart, D. R. P. 250264, Eng. Pat. 568 (1911). 

13. Ehrlich and Bertheim, U. S. P. 986148. 
Benda and " Ber. 41, 1657 (1908). 
Ehrlich and " Ber. 45, 761 (191 2). 

14. D. R. P. 251571, 254187. 

15. D. R. P. 271894, 206456. 

16. Poulenc, Eng. Pat. 21421 (1914). 

17. See 15, and also D. R. P. 216270, 235430, 269886, 269887. 
Kober J. A. C. S. (1919) 442. 

18. Morgan, Organic Compounds of Arsenic and Antimony (1918), p. 226. 

19. D. R. P. 206057; U. S. Pat. 888321 and 907016 (1908). 
Ehrlich, Ber. 42, 36 (1909). 

20. Eng. Pat. 3087, and 9234 (191 5). 

21. Morgan, Organic Arsenic Compounds, p. 256. 

22. Danysz, Compt. Rend. (1914) 159, 452. 



CHAPTER IV 

THE CHEMOTHERAPY OF ARSENIC COMPOUNDS 

The selective action of a compound for certain cells depends on 
the coming together of a particular group in the molecule into 
some sort of chemical connection with the cell substance. In 
1898, Ehrlich (Deut. med. Wock, page 1052) advocated the theory 
that the selective action of a compound for certain cells must be 
based upon the penetrability of the drug. This difference of 
affinity determined whether the drug had greater power to de- 
stroy the parasite or to combine with the protoplasm of the host. 
In the one case it is known as a parasitropic and in the other 
an organotropic substance. After many years of investigation 
of arsenic compounds, the field of arsenic therapy was divided 
into two sections. One was devoted to the study of arsenic in 
the pentavalent form, the other, to arsenic in the trivalent form. 

There are at least three well-defined qualifications that a prep- 
aration must possess and they are summed up as follows: — 

1. The compound must be non-irritant and capable of re- 
maining in perfect solution at the temperature and the alkalinity 
of the tissues. 

2. It must act quickly on the parasites before they can acquire 
a tolerance to the drug. 

3. When the parasites have been expelled from the blood by 
therapeutic doses, there must be no recurrence in a majority of 
cases within some fixed time, which will depend to some extent 
on the particular host and the strain of parasites. 

Pentavalent Arsenic Compounds 

Along these lines of research much work has been carried out 
and certain arsenic compounds have been selected as partially 
fulfilling these requirements. In chemical language we have two 
groups of arsenic compounds, inorganic and organic. For use 



26 THE TREATMENT OF SYPHILIS 

in the present instance, only the organic compounds will be 
considered. We will deal first with the pentavalent arsenic 
preparations and then discuss the trivalent arsenic compounds. 
Arsenic has had some reputation in the treatment of protozoal 
diseases since the time of Fallopius. The compounds containing 
arsenic in the pentavalent condition are: — 

/OH /CH 3 OH OH 



= As— OH = As— CH 3 = 


As ONa 


As 


=0 


\0H \ONa 


/\ 


/N ONa 


Arsenic acid Sodium cacodylate 












\/ 


V 




NH 2 


NHCOCH3 



Sodium arsanilate Sodium acetyl arsanilate 
(atoxyl, soamin) (arsacetin) 

Biological examination shows that all of these products are 
comparatively nontoxic when introduced into the animal system 
until changes take place that liberate arsenic. The arsenic in 
these compounds is liberated very slowly in the system, thus pro- 
ducing the ordinary therapeutic effects of the element. The 
chief objection to this class of compounds is found in the fact 
that they are excreted readily and generally in an unchanged 
form. This means that relatively large doses must be adminis- 
tered to gain beneficial results, while on the other hand the kid- 
neys and liver are suffering from a tremendous oversupply of 
arsenic. Another objection is found in the fact that treatment 
with this class of compounds is followed by degeneration of the 
optic nerve and optic atrophy. These as well as the therapeutic 
action are mainly due to the reduction products which are formed 
in the organism. 

Pentavalent arsenic probably produces cumulative effects 
after repeated doses. Atoxyl was found to be very efficient in 
trypanosomiasis but also it was found that in vitro there was 
little activity for the reason that there was no reduction of the 
arsenic to the trivalent condition. Rohl, and Friedberger (Zeit- 
schrif. Imunitats forschung u. exp. Ther., Vol. I, 1909) Berl. klin. 
Woch. 1909, No. 11, Berl. klin, Woch., 1908, No. j8, Therap. Mon- 



CHEMOTHERAPY OF ARSENIC COMPOUNDS 27 

ats, May, 191 1) state that the curative action probably depends 
on the transformation of the organic pentavalent arsenic com- 
pounds into trivalent preparations which are directly toxic to 
protozoa in the same manner that arsenic pentoxid is partly 
reduced in the organism to arsenious acid. (Binz and Schulz, 
Archiv.f. exp. Path u. Pharm., Vol. II, page 200, 1879.) 

Furthermore, pentavalent compounds cause disturbances of 
the digestive system and nephritis as well as toxic effects on the 
general nervous system. When these compounds are admin- 
istered continuously characteristic symptoms of arsenic poison- 
ing are manifested. The pentavalent organic arsenic compounds 
do not produce any effect on trypanosomes in vitro whereas 
trivalent compounds, either organic or inorganic, show consider- 
able activity. This difference of therapeutic action is probably 
due to the variability of chemical activity. 

It seems to be a well established fact that all arsenical combi- 
nations, which are capable of reacting chemically, are phar- 
macologically active, producing effects which in the last analysis 
are due to the action of the anions, As0 3 or As0 4 . The action 
further might be explained in terms of energy changes in which 
the valency of the element changes from pentavalent to triva- 
lent. A similar theory is found in the case of dyes in which there 
is a certain chromophore group in addition to an anchoring 
group or salt-forming group. This group is one in which nitro- 
gen is involved and is well illustrated by the azo group — N = N — . 

Why Pentavalent Compounds are Unsatisfactory 

In conclusion the pentavalent arsenic compounds are unsatis- 
factory, due to the rapid excretion of the product and to the fact 
that the anatomic changes show degeneration of the optic nerve 
and retinal ganglia as well as the cerebral cell injury. Further- 
more the curative dose is so close to the toxic dose that it ren- 
ders most of these products dangerous, i. e., the ratio of the cura- 
tive dose to the tolerated dose is a small fraction. With a large 
dose for curative purposes it means an increased effort on the 
part of the kidneys and liver to withstand this attack. It should 
not be inferred that this class of compounds do not have any 



28 



THE TREATMENT OF SYPHILIS 



therapeutic action but it is a fact that in most cases they are less 
satisfactory than the compounds containing trivalent arsenic. 

Trivalent Arsenic Compounds 

The trivalent compounds of arsenic are many in number but 
only a few has been of practical use inasmuch as the adaptability 
of many of them has not been entirely satisfactory. From this 
large number a few have been selected because the ratio between 
the etiotropic efficiency and the toxicity has been more favor- 
able. In the case of salvarsan this ratio, according to the Hata 
method, was i : 58. Two products of this type have been used 
very extensively during the past ten years. However, this is no 
indication that other useful products cannot be obtained. A few 
structural formulas will indicate the organic preparations that 
illustrate trivalent arsenic in combination with ring compounds. 





OH 
As = 

S\ OH 




As 


OH 
> = 
OH 


OH 
As = 

M ° H 


A 


u 

NH 2 

rsanilic acid, 
mtavalent 




H 

itr 
:id. 


N0 2 

arsanilic 
pentavalent 


Uno 2 

OH 
Nitro-oxy phenyl 
arsinic acid, 
pentavalent 



As = 



NH 2 
[ 

Amino oxy phenyl arsenoxide. 
Twice as curative as salvarsan 
6 times as toxic. 
Trivalent arsenic 



As = 



As 



X/NH 2 \/NH 2 
OH OH 

Salvarsan base 
Trivalent arsenic 



As = 



r 



NH 2 HC1 J NH 2 HC1 



OH OH 

Salvarsan 



As = As 

\,f] 



As 



sj NH 2 V NH 2 
ONa ONa 

Salvarsan sodium 



As 



\x 



\/NH 2 
OH OH 

Neosalvarsan 



NHCHOHOSX* 



CHEMOTHERAPY OF ARSENIC COMPOUNDS 



29 



Trivalent Arsenic more Potent Therapeutically 

In the case of trivalent arsenic the effective dose can be in- 
troduced with much greater safety and, according to Ehrlich, 
the more powerful therapeutic action is due to the radical con- 
taining the trivalent arsenic, the importance of which was ren- 
dered apparent in experiments with trypanosomes and also to 
the introduction of hydroxy radicals in the para position in the 
molecules, in which the amido radicals are in the ortho position, 
relatively to the hydroxy radicals. In the case of these double 
ring compounds, there is a double arsenic action due to the scis- 
sion of the salvarsan (or neosalvarsan) molecule between the two 
arsenic groups giving the action of two trivalent arsenic mole- 
cules. The chemical change which takes place in the blood is 
probably represented by the following formulas: (Ernest Sie- 
burg — Zeitschr. physiol. client., Vol. 97, p. 53, 1916.) 



As 



V 



As 



NH 2 



As = 



\y 



Protein combination 
NH 2 ^ 



ONa ONa 



OH 
As = 
OH 



OH 



NH 5 



OH 



NH 2 



Amino oxy phenyl 2 amino 3 oxy 
arsenoxide phenyl arsenic 

acid 




r nh 2 



or 



3 oxyl phenyl arsinic acid 



V NH 2 V 

OH OH 

amino phenols 



CHAPTER V 

INDICATIONS, CONTRAINDICATIONS AND EFFICIENCY OF AR- 

SPHENAM1NE 

Particular Indications for Arsphenamine Treatment 

It should not be accepted as a fixed rule that all cases of lues 
are to receive arsphenamine treatment. As elsewhere discussed, 
there are certain definite contraindications to the use of the 
arsenical preparations. It is generally accepted, however, that 
particular indications for the use of arsphenamine can be laid 
down and it is, therefore, advised that the product be utilized in: 

i. All cases of early syphilis possessing distinctive symptoms. 

2. In primary cases as an abortive agent. 

3. In tertiary and latent cases with a positive Wassermann. 

4. In tabes and paresis, congenital syphilis, malignant syphilis, 
painful periostitis and gummata. 

5. In cases in which mercury cannot be used to advantage, 
when the patients become easily salivated or in which, after long 
continued mercurial treatment, the Wassermann reaction re- 
mains positive. 

Contraindications to Arsenical Therapy 

Arsphenamine and neoarsphenamine cannot be used indis- 
criminately upon every luetic person. Therefore a careful 
physical examination of the patient is an important essential. 
If any of the following conditions exist these remedial agents 
should be withheld until the offending obstacle has been re- 
moved if such is possible: 

Recent cases of myocarditis and valvular disease. 

Nephritis, not of syphilitic origin. 

Marked diabetes. 

Advanced tuberculosis. 



INDICATIONS, ETC., OF ARSPHENAMINE 31 

Any diseases of the organs of the thoracic and abdominal 
cavities. 

Persons of very advanced years. 

Persons possessing an idiosyncrasy against arsenic. 

Following acute diseases, especially when depressing sequelae 
are present. 

Dr. H. H. Morton of Brooklyn suggests that salvarsan be 
used with extreme caution in brain syphilis, but directs attention 
to the fact that in acute optic neuritis, choroiditis and inter- 
stitial keratitis, it clears up the lesions with great rapidity. 

The urine of each patient should be examined before the 
administration of the drug and cases showing a renal involve- 
ment should be denied arsphenamine or it should be given in very 
small doses. 

After each injection of salvarsan and neosalvarsan the urine 
should also be examined, so that the physician, at all times, may 
be familiar with the condition of the kidneys. 

A trace of albumin and a few casts may be found in the urine 
the morning after an injection of salvarsan. This should not be 
considered a contraindication unless considerable albumin is 
present and the number of casts on the slide are in excess of ten. 

The Therapeutic Effects of Arsphenamine 

One injection of arsphenamine aids materially in rendering 
the patient non-infectious to those about him. 

The spirocheta pallida disappears from the chancre in from 
twelve to forty-eight hours after salvarsan injection and the 
lesion usually heals in from seven to ten days. 

Condylomata and mucous patches disappear within a few 
days after the injection, as do skin and bone gummata. 

Dr. H. H. Morton says the " effects of salvarsan in malignant 
syphilis are brilliant, especially in the cases which are refractory 
to mercury and iodides." 

Mortality in congenital syphilis has been considerably lessened 
since arsphenamine treatment was instituted. 

Salvarsan relieves the 'lightning pains" of tabes, although 



32 THE TREATMENT OF SYPHILIS 

it cannot restore the nerve tissue which has been destroyed. 
Tabetic and paretic patients are generally much improved by the 
use of salvarsan and in some cases the progress of the disease is 
arrested. 

The intraspinous use of arsphenamine in these cases is advo- 
cated by some and decried by others, but adherents of both intra- 
spinous and intravenous methods seem to be of the opinion that 
improvement usually follows the employment of arsphenamine. 

Arsphenamine's Therapeutic Efficiency 

The efficiency of arsphenamine as a curative agent in the 
treatment of lues has been so definitely established during the 
years of its employment that this subject needs only a passing 
word. 

The testimony of a few authorities will demonstrate to the 
casual reader the place the drug has made for itself in the world 
of therapy. 

Col. E. B. Vedder, U. S. Army {Syphilis and the Public Health, 
p. 259, 1918), says "it has been sufficiently demonstrated that 
salvarsan is a specific in the treatment of syphilis, and while the 
fallacy of our original hopes of a ' therapia sterilizans magna ' is 
now apparent, this drug still remains the most potent remedy 
which we can command. Although it is still possible to treat 
syphilis by mercury alone or in combination with the iodides 
in the later stages of the disease, such treatment is distinctly 
inferior in its results to the proper combination of salvarsan and 
mercury." 

Dr. Loyd Thompson of Hot Springs {Syphilis, p. 232, 1918) 
says "chancres, the syphilodermata, and the syphilomycoder- 
mata heal with startling rapidity, the treponemata sometimes 
disappearing from the lesions within twelve to twenty-four 
hours, while the symptoms of visceral syphilis and syphilis of 
the nervous system usually diminish and may disappear alto- 
gether following its (salvarsan's) use." 

Dr. Cole states in the Ohio State Medical Journal that "sal- 
varsan is the most powerful drug now at the physician's com- 



INDICATIONS, ETC., OF ARSPHENAMINE 33 

mand in the treatment of syphilis and when wisely administered 
is practically free from all danger or marked unpleasantness." 
He adds that herein lies the great value of salvarsan (after an 
injection of salvarsan) that in twenty-four to forty-eight or 
seventy-two hours the acute, contagious lesions on any patient 
will be so changed that he will be no longer a direct menace to 
his friends and society. Cole believes that practically every case 
of cerebro-spinal syphilis with a high cell count in the spinal 
fluid will react well and quickly to salvarsan. He has seen 
''lightning pains" disappear after one or two injections — though 
this is not always true. 

Nine Indications for Salvarsan 

Dr. G. F. Lydston of Chicago states in the Medical Standard 
that he is convinced from careful observation that salvarsan is 
of great value in meeting the following indications: 

First. Prompt removal of genital lesions thus lessening: 
first, the danger of infecting others; second, the danger of detec- 
tion; third, local discomfort; fourth, the danger of serious com- 
plications. 

Second. The prevention or prompt removal of disfiguring skin 
lesions. 

Third. Precocious or malignant syphilis. 

Fourth. Cases resistant to mercury. 

Fifth. Early nerve, brain and visceral lesions, with the excep- 
tion of renal syphilis in which salvarsan is especially dangerous. 

Sixth. Cases of syphilitic cachexia or anemia, which often 
consist of a combination of overtreatment and syphilis. 

Seventh. Syphilis involving the organs of special sense, ex- 
cepting marked lesions involving the retina. The wisdom of 
employing salvarsan here is still subjudice. 

Eighth. Early tabes and, in some late cases, to relieve severe 
pain or involvement of the sphincters. 

Ninth. Infantile syphilis. 

In all cases mercury should be regarded as still our sheet 
anchor in syphilis. 



34 THE TREATMENT OF SYPHILIS 

Arsphenamine as a Prophylactic 

It is a matter of common belief that arsphenamine introduced 
into the system as soon as the initial lesion has manifested itself, 
or before, in the event the recipient feels he has been inoculated 
with the spirocheta pallida, will act as a prophylactic. 

Indeed the ability of arsphenamine to prevent syphilis from 
obtaining a foothold in the system has been exemplified in a 
great number of cases. One of the latest is the report by Dr. A. C. 
Magian {Bull, de VAcad. de Med., Paris, May 20, 1919) to the 
effect that on March 21, 1918, in the French Hospital at Man- 
chester he inoculated himself in the presence of twenty physicians 
with some of the serous fluid from a chancre. Less than an 
hour afterward he was given an injection of arsphenamine, 0.6 
gram. None of the classical symptoms, either local or general, 
which would indicate syphilis, appeared, and although he had 
a Wassermann taken monthly for a year since that time it has 
been constantly negative and he has shown no indication what- 
ever of having the spirocheta pallida in his system. 

We have known cases in which the physician inadvertently 
pierced his skin with a needle which had been utilized for the in- 
jection of salvarsan. As a matter of precaution, the physician 
immediately had himself injected with salvarsan and no signs 
of lues ever developed. 

We are of the opinion that salvarsan used in this way will pre- 
vent syphilis. 

Arsphenamine as a Medicinal Agent in Other than Luetic 
Conditions 

Arsphenamine seems to be of value in conditions other than 
lues. In the tropics it is used as a more or less routine treatment 
in filaria, frambesia, malaria, recurrent fever, tick fever and marsh 
fever, and it has been recommended by some physicians in those 
conditions in which arsenic is indicated, such as psoriasis, leuko- 
derma, pemphigus, and the like. 

Vincent's angina, pyorrhea and " trench mouth " are also 
among the conditions in which arsphenamine has been employed. 



INDICATIONS, ETC., OF ARSPHENAMINE 35 

No particular recommendation is made regarding the employ- 
ment of salvarsan in these diseases, as we have had no experience. 
We are of the opinion, however, that the use of arsphenamine 
will be much more general in the future as research evolves ways 
and means for its use. 

The great war has brought about an entire change in treating 
many conditions. One of the most unique has been described 
by Dr. A. Brechot, of the French Army {Paris Medicate, May 24, 
1 919). He employed neoarsphenamine intravenously for the 
purpose of preventing or curing septicemia, and as an adjuvant 
in furthering and hastening the healing of wounds. He found 
that in such conditions an intravenous injection of neoar- 
sphenamine, 0.3 gram, was followed by great improvement. 
According to the cases which he describes, the action of neoar- 
sphenamine became noticeable at least by the third day, and its 
effect was most beneficial in acute septicemias which were not 
complicated with marked local lesions. 

It was also of benefit in infected wounds in the soft parts which 
were of recent origin and which had become gangrenous. He did 
not obtain beneficial results when neoarsphenamine was em- 
ployed in conditions showing advanced suppuration or where 
there was an enormous amount of gangrene. 

The Comparative Use of Arsphenamine and Neoarsphenamine 

Each of these products has its ardent admirers among physi- 
cians. Some men insist that one, and others the other is the 
drug of choice. Personally, we believe that a great many things 
enter into the matter of a choice between salvarsan and neo- 
salvarsan. Some patients failing to improve with one, make 
marked improvement under the other, and, believing as we do 
that every case of syphilis must be individualized and treated 
according to the particular needs of the affected person, it is 
impossible to make an unqualified statement as to the value of 
one as compared with the other. 

Drs. Wm. B. Trimble and John J. Rothwell of New York 
(/. A. M. A., page 1984, 191 6) made an interesting study based 



36 THE TREATMENT OF SYPHILIS 

on the treatment of no patients, and reached the conclusion 
that neosalvarsan is superior to salvarsan, being much easier 
of administration, less likely to cause severe reaction, and pro- 
ducing a greater percentage of negative results. 

Dr. Oliver S. Ormsby of Chicago (/. A. M. A., page 949, 191 7), 
says that salvarsan and neosalvarsan are the most efficient drugs 
yet discovered in the treatment of syphilis. As to a choice be- 
tween the two, Ormsby believes the extensive use of both pro- 
claims their efficiency, so that individual circumstances with the 
physician and patient must decide which is to be selected. He 
says the apparent preponderance of opinion that salvarsan is 
more efficient is offset to a degree by the difficulties of its admin- 
istration and the more frequent reactions following its use. 

Research work and comparative tests will in the not distant 
future do much toward demonstrating the comparative value 
of the two drugs. 

It is admitted that from the standpoint of the general practi- 
tioner neoarsphenamine is the product of choice. 



CHAPTER VI 

A PLAN FOR ANTILUETIC TREATMENT 

Eternal vigilance is the price of freedom from the spirocheta 
pallida. Immediate, consistent, persistent and proper treatment 
is necessary to overcome the ravages of syphilis. As soon as a 
diagnosis of lues is made, it is the duty of the physician to in- 
stitute treatment. We believe that the great majority of sores 
on the penis are likely to be chancres and we make it a rule to so 
regard all sores that put in an appearance ten days or longer 
after exposure. It is far better to treat a chancroidal case as 
if it were specific than to "slip up" on a case of chancre. It is 
well to bear in mind that many sores diagnosed as chancroids re- 
veal both Ducrey's bacillus and the spirocheta pallida and con- 
sequently demand antiluetic treatment. 

Dark field illumination should be used on all penile sores as 
soon as seen, and little difficulty is experienced in demonstrating 
the presence of the spirochete if it is in the field. This is proof 
positive of the disease. 

In certain instances it is possible to abort syphilis by the most 
vigorous treatment. 

Some authorities advise the excision of the chancre as soon as 
it appears in the belief that, if taken in time, the spirochetes will 
not be able to penetrate the surrounding tissue, and we believe 
it is better to be rid of the lesion if it is so situated that its re- 
moval will cause no deformity. 

Prompt Treatment Demanded 

As soon as the diagnosis has been made, it is our custom to give 
an intravenous injection of 0.3 gram salvarsan or 0.45 gram 
neosalvarsan, or in the case of a woman 0.2 gram salvarsan or 
0.3 neosalvarsan. If well borne by the patient, 0.4 gram sal- 
varsan or 0.6 gram neosalvarsan is given five days later. 



$S THE TREATMENT OF SYPHILIS 

Mercury, preferably one-fourth to one-half grain of the bi- 
chlorid in the form of a collapsule, is given hypodermically in 
the buttock two days after the first injection of salvarsan or 
neosalvarsan and this is repeated three times a week for twelve 
weeks. If an insoluble mercury is desired we use the salicylate 
in collapsules of one grain weekly. 

Salvarsan or neosalvarsan is then administered at seven-day 
intervals until six more doses have been used, making the course 
number eight. 

When taken early, these cases show a negative Wassermann 
and it is our object to keep the reaction negative. One month 
after the last intramuscular injection of mercury a Wassermann 
is taken. If negative, another is taken one month later, and, if 
the result is the same, we wait two months before having another 
examination made. If still negative we have Wassermanns done 
bimonthly for two years, by which time, if the reaction continues 
negative, we feel that a cure has been effected. 

If, on the other hand, the first reaction shows positive, we 
repeat the course of salvarsan and mercury treatment and 
follow this up until a permanent negative is obtained. 

It is not always possible to see our patients at the time the in- 
itial lesion presents itself. Many of the cases of lues which appear 
in the physician's office are beyond the primary stage and abor- 
tion of the disease is out of the question. 

The Treatment of Longer Standing Cases 

It is necessary, in these, to institute intensive treatment, for 
it is on this rock that we must erect our therapeutic structure. 
Many a case has gone down before the gales of disease because 
the house of therapy was built upon the sands of infrequent and 
inconsistent treatment. 

As with the attempt to abort syphilis, we start the patient 
out with 0.3 gram salvarsan or 0.45 gram neosalvarsan (if a 
woman, the dose is respectively 0.2 gram salvarsan or 0.3 gram 
neosalvarsan). Two days later we inject hypodermically in the 
buttock a collapsule of 34 or Y2 grain mercuric bichlorid. Three 



A PLAN FOR ANTILUETIC TREATMENT 39 

days later comes 0.4 gram salvarsan or 0.6 gram neosalvarsan. 
If all is well, salvarsan or neosalvarsan is continued at weekly 
intervals until eight injections have been given and mercury is 
given three times weekly at intervals for twelve weeks, unless the 
insoluble form is employed, in which case the injections are ad- 
ministered weekly. The kidneys must be watched for possible 
irritation. The action of the salvarsan kills most of the spiro- 
chetal pallidas, while the mercury destroys the spirilla? which are 
to be found in organs beyond the reach of the arsenic. 

Four weeks after the last injection of mercury, a Wasser- 
mann is taken. If positive, the salvarsan-mercury course is re- 
peated and is so continued until a negative is obtained. 

If negative, the same routine obtains as in the abortive plan. 

When a case is taken early, one course of treatment is likely 
to result in a negative reaction, and the earlier we start intensive 
treatment the more likely are we to get negatives. 

Iodides Demanded in Tertiary and Latent Cases 

In tertiary and latent cases several courses of treatment may 
be necessary to reach the goal. Potassium iodid must not be 
forgotten in these cases, particularly if gummata or periosteal 
lesions or other manifestations of late syphilis are present. If 
the disease has affected the nervous system it is especially in- 
dicated. To be effective potassium iodid must be pushed in 
heavy doses. The drug should also be used in tertiary syphilis 
with a persistently positive reaction, without involvement of the 
central nervous system. Indeed there are cases, which, though 
apparently clinically cured, are serologically not cured, that is, 
they seem to be permanently positive. Such cases are termed 
"Wassermann fast" and in the light of our present knowledge 
it seems impossible to change these positive cases to negative. 

If a patient shows a negative and later develops a positive, 
we have proof that he still has a focus of infection in his body and 
must be given another course of treatment. 

The provocative injection plays its part as related in the chap- 
ter entitled " Provocative Wassermann Reaction." 



40 THE TREATMENT OF SYPHILIS 

We believe good treatment calls for the use of this procedure 
in early cases. If negative reactions result, we feel that we have 
reason to pronounce a cure. If spirochetal are still in the system, 
we should know it, and the provocative injection is the only 
agent, except time, which will make their presence known. 

In tertiary and latent cases a Wassermann of the spinal fluid 
must be made and the reaction of both blood and spinal fluid 
must be repeatedly negative before the case can be pronounced 
cured. 

Salvarsan and Mercury Necessary 

Dr. C. L. Barewald of Davenport, Iowa, in a paper read before 
the Scott County Medical Society, March 4, 1919, states that 
after using the various preparations on the market he found that 
salvarsan is by far the best, as it gives better results and more 
efficient elimination. He has given more than two thousand 
intravenous injections of salvarsan without experiencing any 
bad results. He emphasizes the fact that syphilis is not cured 
by salvarsan alone and that mercury must be included in the 
treatment. He gives salvarsan once a week for eight weeks and 
at the same time uses mercury, preferably by inunction. 

Intensive Salvarsan Treatment 

Dr. S. Politzer, of New York {Jour. Cut. Dis., Sept., 191 6) is 
an advocate of the most intensive type of salvarsan treatment in 
acute cases. As soon as a positive diagnosis is made, he gives 
three injections of salvarsan in large doses at intervals of twenty- 
four hours, and follows this by a course of eight weekly injections 
of salicylate of mercury. If the treatment is begun after the 
appearance of the rash, this course of salvarsan and mercury 
treatment is repeated after a pause of two months and again 
after a similar interval. After three courses within the first year, 
he suspends treatment if the Wassermann reaction is negative. 

If the treatment is begun a year or more after infection, treat- 
ment should be continued until negative, and two more addi- 
tional courses of treatment given, even though the reaction 
may be negative. 



A PLAN FOR ANTILUETIC TREATMENT 41 

Dr. J. L. Murray of Toledo {Ohio State Med. Jour.) is an 
advocate of a similar method. His plan is to give a small dose 
of salvarsan on three successive days, followed by eight weekly 
injections of salicylate of mercury. 

In the secondary stage, Murray gives these intensive courses 
at intervals of three or four months regardless of the Wassermann 
reaction. 



CHAPTER Vn 

THE TECHNIC OF ARSPHENAMINE ADMINISTRATION 

The Intravenous Administration of Arsphenamine 

The fundamental principle of drug administration is based 
upon the proper usage of the remedial agents which are to be 
employed. Carelessness in technic or lack of necessary informa- 
tion regarding a drug has often seriously injured good prepara- 
tions. 

Three prime requisites stand out as necessary to the satisfac- 
tory administration of a drug: (i) knowledge of the drug and its 
properties; (2) a perfect understanding of the patient and his 
idiosyncrasies; (3) confidence and due precaution on the part 
of the administrator. 

In the injection of any drug by the intravenous method 
rigid asepsis is a most important factor. 

During the past two years over two million doses of arsphena- 
mine have been administered with varying degrees of success. 
After a careful study of the situation in hospital and private 
practice, we have evolved a method of administration, which 
provides safety and precaution in the highest degree for the 
physician and the patient. 

Preparation of the Drug 

The apparatus necessary for the administration of salvarsan 
includes : 

An adjustable bracket or stand, and a table for this stand to 
rest upon. 

Two glass cylinders of 250 c. c. capacity; one for holding the 
solution of salvarsan and the other, distilled water. 




f 

CI 

fc o 



g 



2 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 43 

Rubber tubing leading from each cylinder to a Morton three- 
way stopcock, on the end of which the needle is attached. 

Fordyce or other needles of fine, medium and large calibre, 
the size to be determined by the vein. 

2 c. c. syringe and hypodermic needle for epinephrin. 

An abundant supply of freshly prepared double distilled and 
sterilized water, or 0.4 per cent sodium chlorid solution. 

A tourniquet of rubber tubing or a rubber catheter. 

A glass cylinder (250 c. c.) in which to mix the solution. 

Sterile gauze and sterile cotton. 

A glass funnel for filtering the solution. 

Tincture of iodin or alcohol. 

A bottle of freshly prepared C. P. sodium hydroxid — 15 per 
cent or normal sodium hydroxid — 4 per cent. 

A bottle of collodion for sealing the point of the puncture after 
administration. 

Lastly, the drug itself. 

Apparatus. — The mixing cylinder should be thoroughly washed 
with distilled water and drained for a few minutes, the stopper 
tied loosely to the neck of the cylinder and then the stopper 
and neck covered with a piece of gauze. The combination 
should be sterilized by dry heat and when cool, the stoppers 
inserted without removing the gauze. The gauze is tied around 
the upper part of the stopper so that it can be used as a protection 
to the stopper during its subsequent use in mixing. 

There is no objection to the method of boiling the cylinder for 
twenty minutes in the sterilizer except that it requires additional 
sterile distilled water for rinsing before use. All of the other 
apparatus should be sterilized just before using and extreme 
care should be exercised to avoid using the apparatus while it 
is still hot. The reason for this care is to avoid the decomposition 
of the salvarsan solution before it is used. 

It is a well-known chemical fact that too hot water is one of 
the chief factors in causing decomposition and subsequent re- 
actions. Just before using the apparatus, it should be rinsed out 
with sterile distilled water. 



44 THE TREATMENT OF SYPHILIS 

Distilled Water 

The water problem in the making of salvarsan solutions is a 
question of real importance to physicians, especially to those 
who have occasion to administer arsphenamine at infrequent 
intervals. It is at all times necessary to employ freshly distilled 
water and not that which may be several days or weeks old. 
It is absolutely unsafe to send to a neighboring town for distilled 
water or the 15 per cent sodium hydroxid, and by so doing the 
physician takes a considerable risk. 

It is a well-known fact that water contains many inorganic 
salts as well as much nitrogenous matter. To remove these 
impurities, the process of distillation is used but, through neg- 
lect, some of the water may be allowed to boil over into the side 
tube and thereby vitiate the efforts of purification. Water also 
contains volatile material of a gaseous nature and it is important 
to remove these impurities. Time and space do not permit a 
detailed discussion of a method which will yield what is known as 
"chemically pure" water or "conductivity water." However, a 
general method is presented for securing relatively large quan- 
tities of water suitable for intravenous use. 

Any suitable type of metal distilling apparatus provided with a 
block tin condenser will answer the purpose. A manufacturer of 
chemical apparatus can easily provide this type. In using it, 
care should be used in preventing the possibility of mechanical 
overflow. This provides a roughly distilled water contaminated 
with volatile gases. This grade of distilled water should be used 
for obtaining sterile, freshly glass-distilled water. There are 
several ways of carrying out this procedure. 

The simplest technic is to place the water in any glass-distilling 
apparatus and add calcium oxid or alkaline permanganate to 
absorb carbon dioxid and destroy organic matter. The con- 
tents should be heated to boiling and the distillate collected in a 
flask suitable for later sterilization if the water is not to be used 
as soon as cool. A continuous distillation can be carried on by 
this method. 




Distilling Apparatus 

A simple type for physicians who have no gas, elec- 
tricity or running water, or who lack any one of 
these three conveniences. Description of this ap- 
paratus is found on page 45. 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 45 

A Simple Distilling Apparatus 

In case only a relatively small quantity is to be utilized, omit- 
ting the permanganate, it is well to distill off at least one fourth 
and discard it and to collect the remainder for use. For the 
benefit of those who are limited in their facilities the apparatus 
shown in the accompanying picture is presented. 

This type of apparatus is designed for those who lack gas, 
electricity and running water or any one of the three conven- 
iences. It consists of an ordinary aspirating bottle which may 
be used as a source of water supply by putting ice into water and 
allowing the ice water to flow through the condenser as a means 
of cooling the water vapors. The rest of the apparatus con- 
sists of a pyrex distilling flask suitably connected to a glass 
condenser with a flask for collecting the water. The whole 
apparatus is held in place by a single iron stand with the necessary 
clamps and rings. The apparatus is cheap and very compact as 
well as usable. In fact it may be used by any physician who 
has need for distilled water and has gas and running water 
available. If the water is used within a half hour, it is sterile and 
suitable, otherwise it is necessary to boil the water before using 
and then cool it to room temperature (68-7 7 F.) before using 
it. Under no circumstances should hot water be used with sal- 
varsan or neosalvarsan. 

The Drug 

In manufacturing arsphenamine every care is used in protec- 
ting the drug from undue exposure to oxidation and moisture 
and it is reasonably safe to say that the product is very uniform 
in composition and therapeutic properties. Every ampule is 
carefully examined for any imperfection by the flotation method 
before it leaves the laboratory. During transportation accidents 
may happen to the glass container and in every instance the 
ampule should be placed in 95% alcohol for 20 minutes, to 
detect any imperfections such as a minute crack, which is 
invisible to the naked eye, and at the same time to sterilize the 



46 THE TREATMENT OF SYPHILIS 

ampule. After examination the ampule is dried with a piece of 
sterile cotton or gauze. 

It is imperative that neither the contents of ampules that 
may have been damaged in transport, nor the remainder of 
previously opened ampules should be used, as this involves 
serious danger to the patient. While the ampule is in immersion, 
all the instruments and utensils which are being utilized in the 
administration should be boiled in distilled water. 

The Solution 

Before discussing this most important phase of the technic 
in arsphenamine administration, it may not be amiss to make 
reference to the fundamental principle of therapeutics. All 
therapeutic action is based upon the laws of chemical affinity 
which are in turn governed by the laws of chemical dynamics and 
equilibrium. The demands on the drug are such that it is essen- 
tial the number of reactions should be reduced to a minimum. 
To meet these requirements it is necessary to follow certain 
definite laws of chemistry. 

Some physicians insist on using the drug in concentrated solu- 
tions and pay little attention to alkalinization. Alkalinization 
and concentration are the two most important factors in preparing 
the solution for injection. It is a well-known fact that if solid 
sodium hydroxid is dropped into concentrated hydrochloric 
acid considerable heat is evolved, due to chemical action in 
forming the compound sodium chlorid. The same applies to 
arsphenamine when it is injected into the blood stream. A new 
compound is formed, one in which the proteins of the blood 
stream and the protozoa combine with the arsenical. The 
rapidity and amount of combination are the factors which 
determine whether there will be disturbances in the host. 

The cause of this chemical reaction is to be found in the fun- 
damental laws of energy changes. All of the energy changes are 
easily subdivided into intensity factors, and capacity factors. 
The intensity factor of any form of energy or change tends toward 
equalization of differences which condition develops when the 




Distilling Apparatus 

A simple and inexpensive water still for physicians who have laboratories 
in connection with their offices. 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 47 

rate of injection is very slow and the dilution is great. When 
two substances are brought together, the tendency to equalize 
the difference in concentration and tolerance is adjusted by the 
body. This can only be accomplished when the organism has an 
opportunity to meet these new conditions and establish an 
equilibrium where the drug changes into a soluble compound 
in the body, making due allowance for decomposition of the 
arsphenamine and the rate of elimination. 

To all those familiar with dynamics it will at once be observed 
that the "ideal" solution is the one which gives the most uniform 
results chemically, physically, and therapeutically. The con- 
centrated solutions should yield abnormal results unless the 
time factor is so carefully controlled that an ideal condition is 
obtained. 

Upon this scientific basis it is now suitable to prepare the 
solution. 

Preparation of the Solution 

A dilution of 100 mg. (0.1) to 25 c. c. of water is probably with- 
in the safe limits. The United States Army and the United 
States Public Health Service have recommended a dilution of 
100 mg. in 30 c. c. of water. This is a most conservative recom- 
mendation in view of the fact that there may be other abnor- 
malities existing in the patients. It is also much better to err 
on the side of precaution and conservatism. The size of the dose 
recommended is generally conceded to be a 0.4 gram dose which 
should be given more frequently. This subject will be discussed 
at length in another chapter. 

The ampule of salvarsan should be opened by filing it in two 
or three places near the point where the body of the ampule 
joins the tip. A smart blow on the end of the ampule will break 
it off cleanly. 

About 50 c. c. of room temperature (68-7 7 F.) sterile, freshly 
distilled water should be poured in the mixing cylinder and the 
contents of 0.4 gram ampule lightly scattered on the surface of 
the liquid, using care in maintaining asepsis. The stopper should 
be placed in the flask and gentle agitation follow. The powder 



48 THE TREATMENT OF SYPHILIS 

will dissolve readily in the cold water and when every particle 
is in solution alkali should be added at once, according to the 
table below. 

An ampule of 0.4 gram requires 3.36 c. c. normal sodium hy- 
droxide (4 per cent) or 16 drops of 15 per cent sodium hydroxide. 
It is imperative that the alkali be free from carbonates and 
gelatinous material. For this reason it is best to use freshly 
prepared alkali unless other proper precautions can be taken. 
Again the stopper should be inserted in the mixing cylinder, 
which should be inverted a couple of times, and then the volume 
increased to 100 or 120 c. c. After a gentle shaking, if the proper 
care has been exercised, the solution will be ready for intravenous 
administration. 

The salvarsan solution should be used immediately. In warm 
weather additional care should be used to avoid unusual tempera- 
tures. 

Table of Normal and 15 Per Cent Sodium Hydroxid Necessary 

c. c. of normal NaOH Drops (aver. = .07 c. c.) 
m salt 15% NaOH required 
for disodium salt 

4 
8 
12 
16 
20 
24 
28 
32 
36 
40 

The mechanism of the change taking place during the alkaliniza- 
tion is shown by the following table which indicates the most 
satisfactory form in which the drug should be given. 



igh 


t of drug 


required for dis 


.1 


0.84 




2 


1.68 




3 


2.52 




4 


336 




5 


4.20 




6 


504 




7 


5-88 




8 


6.72 




9 


7-56 


1 





8.40 







Apparatus for Holding Normal Sodium Hydroxtd Solution 

The solution can be kept in the bottle indefinitely and, as it is measured 
out by a burette, absolute accuracy is certain, and perfect alkalinization 
is effected. 

The box holding the apparatus is shown with the sides and top turned 
back and the front cover removed. 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 49 



CHEMICAL TRANSFORMATION OF SALVARSAN 

INTO THE DISODIUM SALT 

Required for Intravenous Injection 
I SALVARSAN 



AS 



AS 




Salvarsan as it appears on market 

H SALVARSAN BASE 
as; 




Sodium Chlorid Na CI is formed 
at this stage of alkalinization 

m MONO-SODIUM SALT 

OF SALVARSAN 




DI-SODIUM SALT 

OF SALVARSAN 




NH. 



SALVARSAN DI-HYDROCHLORIDL 

Yellow Powder about 31.50* Arsenic, 
Soluble in cold water. . 
Acid to litmus. 

Solution not suitable for intravenous 
administration. 



SALVARSAN BASE. 

Precipitated upon addition of 12 drops of 
15* sodium hydroxide solution or 

2.52 cc. of normal sodium hydroxide 
solution per 0.6 gram Salvarsan. 

Insoluble yellow precipitate. 
Causes reactions. 

Not suitable for intravenous administra- 
tion. 



in 

Mono-Sodium Salt of Salvarsan 

Formed upon addition of 18 drops of 
15* sodium hydroxide solution or 

3.78 cc. normal sodium hydroxide solu- 
tion. 

Just soluble in water. 
Clear yellow solution. 
Slightly alkaline to litmus. 
Not suitable for intravenous atkninistra- 
tion. 

IV 

Di- Sodium Salt of Salvarsan 

Formed upon addition of 24 drops of 
15* sodium hydroxide solution or 

5.04 cc. normal sodium hydroxide solu- 
tion. 

Completely soluble in water. 

Clear yellow solution. 

Ready for intravenous administration in 
dilution of 0.1 gram in 30 cc of freshly 
distilled water. 

This is the only form in which Salvarsan 
solution should be used. 



50 THE TREATMENT OF SYPHILIS 

Necessity for Proper Alkalinization 

Some physicians have a tendency to discontinue the alkaliniza- 
tion at the point where the precipitate disappears and the solu- 
tion becomes clear. This is a dangerous procedure for the reason 
that the tendency to form precipitates is greatly increased at 
this alkalinity, since the presence of carbonates, carbon dioxide, 
magnesium and calcium salts combine more readily in this 
condition than in the form of the disodium salt (Myers, U. S. 
Public Health Reports). 

Under these conditions the precipitates not only cause me- 
chanical stoppage in the capillaries, but also extract calcium and 
magnesium from the blood. These last two elements are neces- 
sary for cardiac stimulation and when they are removed the 
blood pressure obviously falls below normal. Such a condition 
aids in allowing the precipitates to collect and block the capil- 
laries. Calcium forms an insoluble salt with arsphenamine and 
this can only be prevented by the use of a more strongly al- 
kalinized solution, namely, the disodium salt. These facts hold 
true with all the preparations on the market at the present time. 
Arsphenamine is a substance which tends to aid blood coagula- 
tion and therefore there is an eminently good reason for the 
proper administration of the drug. 

D. E. Jackson and M. I. Smith of the Hygienic Laboratory, 
United States Public Health Service have shown that there is 
no perceptible fall in blood pressure when the drug is injected as 
it should be. When it is introduced rapidly and in concentrated 
solution, the pressure falls very slowly and collapse may result. 
These facts tend to stimulate the manufacturer to keep up the 
high standard of purity of the product. 

In the early history of the American manufacture of ar- 
sphenamine, some products of poor quality appeared on the 
market but with the present high standards in force, salvarsan 
par excellence is being produced, having the advantages of being 
easily soluble in cold water, of having a uniformly high arsenic 
content, as well as possessing the same therapeutic power of any 
arsenical produced at any time. 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 51 

The Filtering of the Salvarsan Solution into the cylinder 
which is to be utilized for it is urgently recommended. A 
small bit of glass may have chipped off the ampule during the 
filing and found its way into the solution and extraneous matter 
may get into the preparation despite the greatest care. We 
advocate the use of heavy layers of thoroughly sterilized gauze 
for purposes of filtering, rather than to employ absorbent 
cotton. It was formerly possible to get a sterilized cotton 
which was satisfactory for purposes of filtration, but a well- 
known genito-urinary surgeon recently traced some reactions 
following salvarsan administration to the use of absorbent cot- 
ton. 

Upon chemical analysis he discovered the presence of an acid 
which undoubtedly caused the reaction. Calcium-chloro-hypo- 
chlorite (CaCl O CI), incorrectly called chloride of lime, and 
known by the trade name of bleaching salt of lime, is used in 
bleaching cotton. The chlorite present in the cotton was due to 
the chlorine contained as natural chlorites and probably to 
chloride of lime remaining in the cotton due to incomplete neu- 
tralization and washing in the process of preparation of the 
absorbent cotton. The acid present was undoubtedly due to the 
formation of either a little hydrochloric acid from the bleaching 
salt of lime by the action of sulphuric acid, by which the cotton 
is treated to neutralize the alkalinity of the bleaching lime, or to 
the presence of both hydrochloric and sulphuric acids. 

Physicians using absorbent cotton who get reactions would 
do well to make a chemical analysis of their cotton. 

After filtering the solution of salvarsan into one cylinder we 
next run 100 or more c. c. of freshly distilled sterilized water into 
the other cylinder, the rubber tubing having been previously 
attached to each cylinder. The tubing should then be raised 
up and down a sufficient length of time until all the bubbles of 
air have disappeared. The tubing can be squeezed in various 
places so as to make certain no air is present. The needle 
should be attached by short rubber tubing to the Morton three- 
way stopcock, with a window made of glass tubing between the 
Stopcock and the needle, so that when the puncture is made the 



52 THE TREATMENT OF SYPHILIS 

operator can ascertain his whereabouts in the vein by the back 
flow of blood. 

Preparation of the Patient 

After having determined that there are no contraindications 
to the administration of arsphenamine or neoarsphenamine, the 
preparation of the patient for treatment should begin the night 
before the administration, when an active catharsis must be 
induced. At the time of the injection, the gastrointestinal tract 
must be entirely clear. If the treatment is to be given in the 
morning, the patient should eat no breakfast and, if in the after- 
noon, no luncheon. We make it a rule to allow no food in the 
stomach for at least six hours before the injection, thus insuring a 
clean intestinal tract. There is no objection to a cup of weak 
tea at meal time, but no solid food of any type should be per- 
mitted. 

It is necessary to examine the urine before each injection. 

When these details have been carried out and the patient is 
ready for the administration of the drug, he should be laid in a 
recumbent position on a surgical table or, if the injection is given 
at home, on a bed. If the surgical table is used, it is very easy to 
affix an arm thereto, upon which the patient's arm can rest. 
This gives the operator the advantage of having the field of 
operation perfectly steady at all times. 

The Choice of the Vein 

The vein of choice is the cephalic just below the junction with 
the vena mediana cubiti, as at this place a level spot is offered, 
whereas a little higher up the bend of the elbow is encountered 
with its attendant inconvenience for the entrance of the needle. 
If for any reason this vein is not available, the basilic, just above 
or below the junction with the median antibrachial, offers the 
most attractive site of entrance. 

Sometimes the accessory cephalic is large enough for the easy 
insertion of a needle and as a dernier ressort the physician is some- 
times compelled to use the median antibrachial near the wrist or 
one of the oblique branches connecting the basilic and cephalic. 




S-i - 

OJ o 
> o 

a 



«-» a 



■ts ^ d 

all 

*^ 

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u *& bD 

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TECHNIC OF ARSPHENAMINE ADMINISTRATION 53 

The veins near the wrist are usually so small that much skill 
is required for the introduction of a needle of fine calibre. 

When the vein has been chosen, the arm is thoroughly cleansed 
with alcohol or iodin well over and around the point of the in- 
tended puncture. The area should be covered with sterile gauze 
until the actual injection is made. 

The patient's arm should rest on sterilized towels and it will be 
much easier to put a sterile gauze pad just below the spot where 
the injection will be made, so that the blood can be caught. It 
is needless to observe that the operator and his assistant must 
"wash up" as for any operation. 

The tourniquet is then applied to the patient's arm two or 
three inches above the bend of the elbow joint, and an oval body 
such as the wooden box in which salvarsan comes is placed in his 
hand to assist in bringing out the vein. He is told to clench the 
fist as if to strike a blow and within a few seconds after the 
application of the tourniquet (which can be either a rubber 
catheter or a piece of ordinary rubber tubing) the vein should 
stand out sufficiently large to enable the operator to proceed. 

There is a difference of opinion as to making the injection with 
a needle attached to the tubing or without it, and this is a matter 
which an operator must decide for himself. When the needle is 
attached he can observe the back flow through the window. 
When it is unattached, there is no difficulty in ascertaining the 
presence of the needle in the vein by the backward flow. We 
prefer the latter method. 

Introduction of Needle into Vein 

Fixing the chosen vein between the thumb and finger of one 
hand, with the needle between the thumb and index finger of the 
other hand, the point of the needle should be inserted into the 
vein as near the middle thereof as possible. When entrance 
has been effected, the needle should be slowly moved from side 
to side to make certain that the wall of the vein has not been 
pierced. If the vein is very large, it is better to enter at an angle, 
so there may be no tearing of the lumen. 

As soon as the physician satisfies himself that he has placed 



54 THE TREATMENT OF SYPHILIS 

the needle squarely in the vein, the tourniquet should be released 
and the rubber tubing attached. The stopcock is then opened to 
permit the entrance of about 25 c. c. of distilled water into the 
vein. 

The Introduction of Distilled Water before the Arsphenamine 

The purpose of the introduction of the distilled water first 
is that if there should be any leaking around the point of entrance 
caused by the tearing of the vein the use of distilled water will 
obviate any pain, or possible inflammation caused by infiltra- 
tion. The arsphenamine solution, if allowed to leak out, would 
cause a burning sensation and considerable difficulty might re- 
sult from an infiltration. After the injection of 25 c. c. of dis- 
tilled water the stopcock is turned and the salvarsan introduced 
very slowly, the operator allowing at least two minutes for each 
decigram of salvarsan. When the full amount has been injected, 
he should switch back to the distilled water and thus wash out 
the vein. 

After the needle has been removed it is better for the patient 
to hold his hand perpendicularly for a short time, pressing a 
pledget of sterile gauze over the point of entrance. When the 
bleeding has entirely stopped a drop of collodion should be placed 
over the point. There is no necessity to bandage the arm. 

The patient should be kept in a recumbent position for from 
fifteen minutes to an hour and he should remain quiet the re- 
mainder of the day. We have given in our office many injections 
of salvarsan to patients who have gone long distances — some as 
far as one hundred miles — within an hour after the injection. 
This practice is not recommended, however, and is only advisable 
in times of emergency. As reactions may follow several hours 
after the injection it is always well to have the patient near at 
hand. 

Helpful Hints in Treatment 

There are many small points in connection with the injection of 
arsphenamine which, if carried out, are helpful. One of the first 
is the use of sharp needles. We suggest a very sharp, short- 




u 

(2 



o _ 



<u .a 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 55 

beveled needle instead of one with a long sharp point, as the long- 
pointed type may catch in the wall of the vein and cause a 
leak. A dull needle is not only likely to tear the vein and cause 
subsequent infiltration, but the pain attendant upon its use is 
discouraging to the patient. The use of such a needle is partic- 
ularly difficult when the patient happens to be of a neurotic type. 

If the veins do not stand out perfectly with the application 
of the tourniquet, a few smart slaps on the arm over the intended 
point of entrance will often have the desired effect. Another 
method of enlarging the vein is to have the patient, with his arm 
very rigid, bend his wrist forward so that the clenched first will 
be at an angle of 45 to the forearm. 

Some small veins can be brought out by the application of 
sterile gauze wrung out in hot water. 

Walking up three or four flights of stairs or bending over and 
touching the floor with the ringers, without flexing the knees, 
are also recommended for bringing out the veins. 

In injecting a vein, if for any reason the blood does not flow 
freely and the operator desires to use the same vein higher up it 
is well to leave the first needle in place and make the injection 
through another needle, as by the removal of the first needle a 
hematoma may result. 

We desire to warn particularly against using the stylet of the 
needle to cleanse a needle which may seem to be clogged up. 
An embolism is likely to follow such prodecure. 

Too rapid injection of salvarsan may bring about a feeling of 
dyspnea and oppression, due to the over-dilution of the blood in 
the right heart, with the result that the blood going into the 
lungs contains an insufficient amount of oxygen. 

At times it is not possible to have an assistant when administer- 
ing salvarsan and the removal of the tourniquet may prove some- 
what awkward to the operator. The patient, if a man, can very 
easily be taught to grasp his undershirt or, if he wears the sleeve- 
less type, the outside shirt in one finger and roll it up so tightly 
that the circulation will be completely impeded. This makes 
a most efficient tourniquet and can be released upon a word from 
the physician. 



56 THE TREATMENT OF SYPHILIS 

The Use of Vasodilators 

Dr. George E. Barnes of Herkimer, N. Y. {Boston Medical & 
Surgical Journal, May 15, 1919), offers an ingenious method for 
facilitating the insertion of the needle into small veins by the 
use of vasodilators. He recommends nitroglycerin as the par- 
ticular product to be used. Barnes believes that, while this 
acts acutely, there is also good reason to use other remedies for 
a continual state of normal tension of the vessels and suggests 
such products as gelsemium, cannabis, Pulsatilla, conium, lu- 
pulin, cramp bark and cactus. He suggests that the nitro- 
glycerin be taken in the proper dosage in tablet form, chewed up, 
dissolved in the saliva and swallowed. Such a drug, however, 
should not be used until it is ascertained whether or not the 
patient is likely to have a reaction. 

A Window over the Vein 

Dr. E. G. Ballenger, of Atlanta {Genito-Urinary Diseases and 
Syphilis , p. 477, 1913) has a unique method of inserting a 
needle into a vein which is not easily palpable or visible. By 
means of a small round stiletto he had fashioned for the pur- 
pose, a window is made in the skin over the vein, the skin first 
being pulled to one side, so that the stiletto will not injure the 
vein. This leaves a window twice the size of the needle directly 
over the vein. With the vein well distended and often visible 
through the hole, it is easy to slip the needle through the opening 
directly into the vessel. 

Concentrated Injections of Arsphenamine 

Some men of great eminence are utilizing salvarsan in the 
concentrated method. Dr. E. L. Keyes, Jr., in his splendid book 
on Urology observes, page 827, that "the original technic calls 
for the administration of 300 c. c. of fluid. At present the usual 
allowance is 10 c. c. of distilled water for every decigram of the 
drug to be injected. The dose for the adult male is three or 
four decigrams; for the adult woman, three decigrams; for the 
infant, one centigram. . . . 




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TECHNIC OF ARSPHENAMINE ADMINISTRATION 57 

"The injection is made either by gravity or with a 30 c. c. 
piston syringe or by a syringe to which is attached a three-way 
stopcock and one rubber tube leading into the bottle containing 
the salvarsan, while the other leads to the needle in the patient's 
arm. Whatever the method employed, it is essential that the 
salvarsan be given slowly and that at least five and preferably 
ten minutes be taken for the injection of the 30 c. c. Therefore, 
the gravity method is the safest." 

The concentrated method of salvarsan introduction is doubt- 
less a safe one in the hands of so experienced and skillful an 
operator as Dr. Keyes, but for the average medical man, part 
of whose time must necessarily be given to other lines of medicine, 
we feel that the concentrated method is unsafe. Dr. Keyes' 
technic is presented to show that the concentration of the fluid 
is not regarded as dangerous by one of our most eminent col- 
leagues, but the earnest suggestion is made that men who have 
not had as much experience in the administration of salvarsan 
as Dr. Keyes do not emulate his example. 

Dr. Theodore H. Smith, of Detroit {Jour. Mich. State Med. 
Soc, April, 191 7) believes that concentrated solutions of sal- 
varsan are more effective than dilute ones in that the salvarsan 
in the concentrated solution is more slowly excreted, but he ad- 
mits that the one objection to this method is the urgent necessity 
of a perfect technic in the intravenous injection itself. He says 
that if the needle does not lie accurately within the vein, a small 
amount of the concentrated solution entering the perivascular 
tissue will produce results even more dangerous than with the 
more dilute solution. 

Injection of Salvarsan into the Superior Longitudinal Sinus 

One of the largest venous channels in the body is the longi- 
tudinal sinus lying at the posterior angle of the anterior fontanel. 
Through this medium salvarsan can be injected. It has been 
used for a number of years for the injection of saline solutions and 
for blood transfusion. 

Dr. Louis Fischer of New York, read a paper on "The Value 
of the Longitudinal Sinus in Transfusion and for Rapid Medica- 



58 THE TREATMENT OF SYPHILIS 

tion" before the Section on Diseases of Children of the American 
Medical Association in June, 1918. He expressed himself as 
thoroughly convinced that the difficulty of entering a vein the 
size of the median basilic or even the femoral, in infancy, makes 
the longitudinal sinus the route of choice for the introduction of 
any medication into the system of an infant or for transfusion. 

Dr. Fischer has perfected a technic which physicians can well 
follow. He wraps the infant in a mummy bandage, well pinned, 
so that the arms and legs are confined, and places the child flat 
on its back. The head is steadied on both sides by an assistant 
while the needle is inserted into the sinus. He finds that he can 
enter through the anterior fontanel until the child has reached 
the end of its second year. As the sinus grows wider toward the 
back of the head, Fischer recommends the point of entrance to 
be as far posterior as possible. 

The needle is pushed through the posterior angle of the fon- 
tanel and directed downward and backward in a line with the 
sagittal suture. The sinus is very superficial and there is no 
need of entering deeper than 1 or 2 mm. For this purpose a 
sharp-pointed needle Y2 inch long of 20 or 22 gauge is best 
adapted. When the needle penetrates the sinus, resistance is 
lessened and the same sensation is observed as when a needle 
enters the dura mater in performing a lumbar puncture. 

In giving salvarsan by this method, Dr. Fischer advises that 
it be administered by gravity slowly. A cylinder from 30 to 
100 c. c. capacity can be used. One end of a piece of rubber 
tubing is attached to the cylinder and the other end has a con- 
necting tip which fits into the needle. A stopcock should be at 
the end of the cylinder or near the end of the tubing. The 
needle is inserted into a small syringe attached. By a slight 
aspiration the physician can determine whether the sinus has 
been entered; if so, the syringe is detached and the apparatus, 
which has been filled and the air expelled, is connected. 

The child should be watched carefully and its color, pulse and 
respiration noted. 

Dr. Fischer is of the opinion that there is no danger of losing too 
much blood by the puncture, even though a large needle is used. 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 59 

Dr. Vincent of Boston warns against injecting too rapidly 
lest increase of intra-cranial pressure cause vomiting and dis- 
turbed respiration. These difficulties are soon overcome when 
the flow of blood has been temporarily checked. Air pressure in 
the tube must be released by detaching the syringe before the 
needle is withdrawn. 

Blood Precipitates 

Danysz and Fleig have written extensively about the forma- 
tion of precipitates when salvarsan is introduced into the blood 
by the intravenous route. The cause of many reactions has 
been traced to the use of acid and under-alkalinized solutions. 

Herring {Munch Med. Woch., Vol. 57, No. 50, 191 1) has shown 
that in rabbits the acid solution is twenty times as toxic and in 
dogs ten times as toxic as a properly alkalinized solution. When 
an acid solution is introduced into the blood stream a yellow, 
insoluble precipitate is formed and this prevents the flow of the 
blood through the capillaries. In this condition calcium and 
magnesium are precipitated as insoluble salts of salvarsan. The 
removal of these elements from the blood stream has a tendency 
to reduce the blood pressure and in the presence of the insoluble 
blood precipitate, it is practically impossible for the blood to 
circulate through the capillaries. 

If a properly alkalinized solution (disodium salt) is used, no 
fall in blood pressure is observed and, in addition, the formation 
of precipitates is almost entirely eliminated. If the monosodium 
salt is used, the carbonates, sulphates and alkaline phosphates 
cause a precipitation of the drug very easily on account of the 
hydrogen ion concentration, resulting from the chemical com- 
binations. An alkaline solution (many hydroxyl ions) tends to 
eliminate these conditions. The isolation and chemical analysis 
of these blood precipitates will be found in a recent U. S. Public 
Health report. 

The Intramuscular Administration of Arsphenamine 

The intramuscular method of injection was in the early days of 
salvarsan hailed as an easy and convenient manner of introducing 



6o 



THE TREATMENT OF SYPHILIS 



the drug into the system. The pain attendant upon the injection 
proved to be a raison d'etre for discarding the method in favor 
of intravenous medication on the part of the great majority of 
salvarsan users. The intramusular method is still employed in 
such cases as present no suitable veins, and again by physicians 
who believe the results from the intramuscular method excel 
those from intravenous introduction. 

Col. Charles F. Craig, U. S. Army (The Wassermann Test, 
p. 1 80, 1918) has demonstrated the truth of this assertion by a 
study of 500 cases, of which 209 were treated by the intramus- 
cular injection of the alkaline solution, 249 by the intravenous 
injection of the drug, and 42 by combined intramuscular and 
intravenous injections. 

This table illustrates the effect of the method of administra- 
tion upon the Wassermann reaction: 



Method of 


Total 
Cases 


Became Negative 


Remained Positive 


Administration 


Number 


% 


Number 


% 


Intramuscular .... 

Intravenous 

Combined 


209 

249 

42 


159 

101 

28 


76.0 

44-5 
66.6 


50 

148 

14 


24 

55-5 

33-3 


Totals 


500 


288 


57-6 


212 


42.4 



It will be observed, from a study of the table, that the effect 
of intramuscular injections of salvarsan upon the reaction is 
much more pronounced than other methods of administration. 
This method of administration has been almost abandoned by 
the profession, and in the army it has been entirely replaced by 
the intravenous method, owing to the pain and complications 
that follow the injections and the time lost in hospital. However, 
there is no question in Craig's opinion that the intramuscular 
method is infinitely more efficient in treatment than the in- 
travenous, as shown by the results upon the Wassermann test, 
for of the 209 cases so treated, most of them receiving but one 
injection of 0.6 gram salvarsan, 159, or 76 per cent became nega- 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 61 

tive, and fewer cases treated by the intramuscular method re- 
lapsed than when treated intravenously. 

The figures given for the intravenous method are below what 
they should be for the reason that the majority of the cases 
studied only received one intravenous injection. Further 
observations upon this method of administration and its effect 
upon the Wassermann reaction have shown that with from 
three to five intravenous injections the results are as good as 
those obtained with the intramuscular injections, but the data 
here given are sufficient to show that the Wassermann reaction 
can be rendered negative by only one intravenous injection in at 
least 40 per cent of the cases. 

Intramuscular Method Superior to the Combined 

The effect upon the reaction of the combined intransmuscular 
and intravenous method of using salvarsan was determined in 
42 cases, of which 66 per cent became negative, thus indicating 
that the results were not as good with the combined method as 
with the intramuscular method alone. However, this result was 
due to the fact that a number of the intramuscular cases had two 
or even three injections of salvarsan, and it is considered that one 
intramuscular injection of the drug is equal to at least three 
intravenous injections so far as the effect upon the Wassermann 
test is concerned. 

As should be expected, the effect of treatment with salvarsan 
upon the reaction increases with the number of doses of the drug 
that are administered, regardless of the method of administra- 
tion. Of 200 cases receiving one intramuscular injection of sal- 
varsan of 0.6 gm., 152, or 76 per cent became negative, while of 
9 cases receiving two intramuscular injections, 7, or 77.7 per 
cent became negative. There is little difference between these 
two groups of cases so far as the apparent effect upon the Wasser- 
mann test is concerned, but the number of cases receiving two 
intramuscular injections is too small to allow of our basing upon 
them any accurate statistics, as a large number of cases would 
undoubtedly give a higher percentage in this class of cases. 

Of the cases treated by the intravenous method, 177 were 



62 THE TREATMENT OF SYPHILIS 

given one intravenous injection of 0.6 gm. of salvarsan, and 72, 
or 40.6 per cent became negative; 52 were given two intravenous 
injections of the same dose, of which 22, or 42.3 per cent became 
negative; while 10 cases were given three intravenous injections, 
of which 7, or 70 per cent became negative. There was but little 
difference in the percentage of negative results obtained in those 
given one and two intravenous injections; and it will be noted that 
two intravenous injections did not have as much effect upon the 
Wassermann reaction, as one intramuscular injection. The per- 
centage of negative results obtained with three intravenous in- 
jections, however, approaches closely to that obtained with one 
intramuscular injection, and justifies the assertion, based upon 
this obvious experience, that one intramuscular injection is 
equal, in its effect upon the Wassermann reaction, to three in- 
travenous injections of a salvarsan. 

Preparation of Arsphenamine for Intramuscular Use 

Several methods of preparing salvarsan for intramuscular in- 
jection are in vogue. 

Ehrlich set forth the following method for the preparation of 
alkaline solutions for both intramuscular and intravenous in- 
jection: 

Ehrlich's Method 

"Into a narrow-necked, glass-stoppered, sterile, graduated 
glass cylinder of 300 c. c. capacity, 30 to 40 c. c. sterile freshly dis- 
tilled water of not more than room temperature are measured. The 
salvarsan, for example 0.5 gram, is sprinkled on the surface of 
the water and dissolved by vigorous agitation. To the solution, 
after it has become absolutely clear and no undissolved particles 
can be seen, 19 drops of 15% sodium hydroxid solution are 
added by means of a pipette, drop by drop. This causes a pre- 
cipitate which dissolves on shaking. The clear yellow solution 
is now filled up to 250 c. c. with sterile 0.5% saline solution pre- 
pared from chemically pure sodium chlorid and sterile Freshly 
distilled water. 

" Salvarsan solutions must always be freshly prepared. In the 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 63 

preparation of the alkaline solution it is imperative to observe 
that the salvarsan must be completely dissolved in distilled water 
{not saline solution), at ordinary temperature and that the solu- 
tion does not show any gelatinous particles whatever before 
the sodium hydroxid solution is added. The sodium hydroxid 
solution is not added gradually, but at once. The precipitate 
produced thereby must be completely dissolved prior to the 
further dilution of the alkaline concentrated salvarsan solution 
with 0.5% saline solution. The sodium chlorid must be 
chemically pure. Tap or spring water is unsuitable. Hot water 
must NOT be used in preparing the solution of salvarsan. Should 
the solution not be quite clear or become slightly turbid after 
a few minutes, a few more drops of sodium hydroxid solution 
should be added, a drop at a time and waiting 2 or 3 minutes 
after each drop to see if this quantity suffices to clear the solu- 
tion. Each 50 c. c. of this solution contains 0.1 gram salvarsan. 

"If no graduated glass cylinder is at hand, the concentrated 
salvarsan solution may be prepared in a small glass-stoppered 
flask, and after the addition of sodium hydroxid solution and 
complete clarification, poured into the saline solution. The solu- 
tion should be filtered if necessary. 

" Intramuscular Injections may be made with the alkaline 
solution as above described, but in this case only about 5 c. c. of 
fluid are required. For its preparation one proceeds by well 
triturating in a sterile mortar, for instance 0.5 gram salvarsan 
with 19 drops of 15% sodium hydroxid solution and then dilut- 
ing with distilled water to the desired volume. The injection 
is made into the upper exterior sections of the gluteal muscles. 
The injection should be made deeply but very slowly, so as not to 
cause hemorrhage. The neighborhood of the sciatic nerve must 
be carefully avoided. Intramuscular injections may also be 
made with simple triturations of salvarsan in fatty oils 1:10 
(Oleum Amygdal. dulc, Oleum Sesami, Oleum Olivae). 

"In all cases the area of the injection must be previously dis- 
infected with iodin-benzene or tincture of iodin. After intra- 
muscular application the injected fluid should be distributed by 
massage. 



64 THE TREATMENT OF SYPHILIS 

"In sensitive persons the site of injection may be com- 
pletely anesthetized by a previous injection of 2 c. c. of a 1% 
novocain solution. Hydropathic measures, as moist compresses, 
hip-baths, etc., or the application of warm compresses, may be 
successfully employed to prevent afterpain. The internal ad- 
ministration of pyramidon has proved very efficacious." 

The Alt Method 

The Alt alkaline solution method is: "Ten c. c. of sterile dis- 
tilled water are placed in a beaker of about 50 c. c. capacity, 
the salvarsan added and triturated with a glass rod until com- 
pletely dissolved. Normal (4 per cent.) sodium hydroxid solu- 
tion is now added in the proportion of 0.5 c. c. to each 0.1 gram 
of the drug. The stirring is continued until a precipitate is 
formed and is partially redissolved. The alkali solution is now 
added drop by drop until the opacity nearly clears. It is not 
desirable to permit the solution to become completely clear, as 
such a solution is more irritating to the tissues than the slightly 
tubid solution. The total volume is now made up to 20 c. c." 

The Michaelis Method 

The neutral suspension of Michaelis is prepared as follows: 
"The salvarsan is dissolved in a solution prepared by adding 
0.3 to 0.6 gram of sodium hydrochlorate to 16 c. c. of very hot 
sterile distilled water in a wide-mouthed graduated cylinder. 
From 3 to 5 c. c. of normal sodium hydroxid solution are added 
and the mixture thoroughly stirred. Three drops of a 0.5 per 
cent, solution of phenolphthalein in 70 per cent, alcohol are 
added as an indicator, which causes a red color to develop. Then 
1 per cent acetic acid solution is added, drop by drop, until the 
red color disappears. The salvarsan is precipitated as fine yellow 
floculi and finally a few drops of the normal sodium hydroxid 
solution are added to recolor slightly the phenolphthalein. The 
solution is then ready for injection." 

Oily Emulsions 

Oily emulsions are also employed intramuscularly to advan- 
tage. The firm of Hynson, Westcott & Dunning, of Baltimore, 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 65 

puts out ampules of salvarsan in oil ready for injection, which 
have met with favor at the hands of advocates of intramuscular 
medication. 

British Army Method 

Lt. Colonel L. W. Harrison, R. A. M. C, in charge of the Mili- 
tary Hospital, Rochester Row, England, reports favorably 
{Brit. M. J., May 5, 191 7) on the use of the intramuscular method 
of neosalvarsan administration. He used neosalvarsan dissolved 
in 10-15 minims of distilled water and injected into the gluteus 
medius muscle. This gave a fair amount of pain with some lame- 
ness after, but when accompanied by a hypodermic injection of 
morphin it proved as comfortable as any other method. He also 
utilized the same amount in deep subcutaneous injection, made 
under the fascia covering the gluteus medius muscle. This was 
less painful immediately afterward, but often caused the forma- 
tion of a tender lump on the site of the injection some days later. 

Another method was the intramuscular and deep cutaneous 
injections of neosalvarsan emulsified in creo. camph., melting 
point, 20 C. There was some pain for a few hours afterward but 
as a rule the patient would allow the site of the injection to be 
massaged vigorously the following days. 

The most useful method was the injection of six decigrams 
neosalvarsan dissolved in 1 c. c. of a 4 per cent, solution of sto- 
vain and made up to 2 c. c. with creo. camph., melting point, 
1 5 C, or with camph. phenique. This was the most comfortable 
injection to use. It was made about a point three finger breadths 
below the crest of the ilium on a line joining the tuber ischii with 
the point on the crest of the ilium, which is perpendicularly above 
the great trochanter, when the patient is upright. 

As a result of these injections, Harrison feels that the intra- 
muscular or subcutaneous method is superior in immediate 
therapeutic effect to the intravenous, that the spirochetes dis- 
appear from syphilitic lesions just as rapidly after the first in- 
tramuscular as after the first intravenous injection, and that the 
Wassermann reaction is more quickly influenced. 



66 THE TREATMENT OF SYPHILIS 

An American Method 

Still another method which has been successfully utilized by- 
some American physicians is to mix i oz. each of a 2 per cent 
novocain solution and chemically pure glycerin. To 4 c. c. of 
this combined mixture are added the contents of an ampule of 
neosalvarsan. They are thoroughly mixed together, antisepti- 
cally of course, and 1 c. c. is injected through each of four needles 
— two in each buttock. By the utilization of the four needles, 
there is not so much foreign substance in the given parts of the 
muscle and there seems to be less likelihood of trouble. The 
novocain anesthetizes the part for some time and takes away 
the initial sting of the injection. 

After Treatment 

In England and on the Continent it is the habit, after giving 
an intramuscular injection, to cover the surrounding parts with 
sterilized absorbent cotton fixed with elastic collodion. The 
patients were instructed to rest in bed for twenty-four hours and, 
according to various reports, the majority of them complained 
only of stirTness in the hip and thigh and occasionally of pain in the 
lower extremity. 

Some physicians also utilize a clay dressing, like antiphlogistine, 
in place of cotton. It is their custom to cover the entire gluteal 
surface with a thick layer of properly heated antiphlogistine and 
to cover this with gauze, and over that absorbent cotton. This 
application seems to work well following the intramuscular in- 
jection and, not only aids in the prevention of pain and to a con- 
siderable extent prevents any abscess formation, but enables the 
patient to attend to his ordinary affairs. 

Intramuscular Methods not Popular 

Notwithstanding the experience of Col. Harrison, as above 
recounted, the vast majority of practitioners seem to prefer the 
intravenous procedure of adrninistering salvarsan and neosal- 
varsan. Their reasons are based upon the fact that the local 
disturbances, accompanied by pain and possible abscess, when 



TECHNIC OF ARSPHENAMINE ADMINISTRATION 67 

the intramuscular method is employed, seem like a needless 
punishment of the patient. Moreover, the patients themselves 
demur and express a preference for any treatment which will 
eliminate the suffering so commonly accompanying the intra- 
muscular introduction of arsenical products. 

Administration of Arsphenamine by the Rectum 

More or less has appeared in the medical press concerning the 
introduction of salvarsan into the system by way of the large 
intestine. Various means have been advocated for the introduc- 
tion of salvarsan in this manner. This method is not advocated 
by medical writers except in children and adults whose veins are 
exceedingly difficult of entrance. We have employed it with 
success in different individuals, whose veins have not been utiliz- 
able. 

The patient has the usual pre-salvarsan preparation, so far 
as the gastrointestinal tract, etc., is concerned. In addition the 
lower bowel must be thoroughly cleansed by an enema. The 
patient is then placed on the table in the Sims or genupectoral 
position and a sterilized catheter is inserted into the rectum a 
distance of six inches. 

Our technic has been to slowly and carefully emulsify salvarsan 
in 1 ounce of olive oil by thoroughly stirring the powder into the 
oil with a glass rod. When this has been properly accomplished 
the oily emulsion is drawn up into a sterilized glass syringe and is 
forced through the catheter into the rectum. Another ounce of 
olive oil is then introduced in a similar way through the same 
catheter. The catheter is withdrawn and the patient is allowed 
to remain upon the table for one hour. If the injection is given 
at the home it is better to keep the patient in bed for several 
hours so as to prevent any escape of the salvarsan emulsion. 

It will be observed that arsphenamine employed in this manner 
is not alkalinized by sodium hydroxid but is put directly into the 
olive oil. 

Some physicians employ salvarsan for rectal injection by mak- 
ing an aqueous solution, but we prefer the oil on account of its 
blandness and because there is less opportunity of irritating the 



68 THE TREATMENT OF SYPHILIS 

mucous membrane of the intestine. This method has been fol- 
lowed in giving weekly injections to patients and we have had 
no complaint of bowel irritability. 

When aqueous solutions are used sodium hydroxid is employed 
exactly as in making up a solution for intravenous injection. 
The amount of distilled water should be about 30 cubic centi- 
meters. 

Patients remaining in the genupectoral position any length 
of time complain of great weariness, so that after ten minutes we 
permit the patient to assume the Sims position. 

The physician must exercise care not to permit any escape of 
the injected contents. 

We have seen no occasion to utilize opium or any of its deriva- 
tives in this form. Some operators have added a little laudanum 
for its soothing effect, but our experience has not made this neces- 
sary. 



CHAPTER VIII 

THE TECHNIC OF NEOARSPHENAMINE ADMINISTRATION 

There are two methods of introducing neoarsphenamine into 
the system, one, the dilute, and the other, the concentrated. The 
preparation of the patient for either method is the same as that 
for arsphenamine, and every detail as set forth in the preceding 
pages, as to the physical condition of the patient, the gastro- 
intestinal toilet, and the urinary examination, should be carried 
out in its entirety. 

The choice of veins is the same. 

Dilute Intravenous Administration of Neoarsphenamine 

The apparatus necessary for the dilute administration of 
neosalvarsan is practically identical with that for salvarsan, 
with the exception that the use of sodium hydroxid is prohibited. 

The ampule of neosalvarsan should be immersed in 95 per cent 
alcohol for twenty minutes and all the instruments and utensils 
should be boiled in distilled water. When these latter are suffi- 
ciently cool, the amount of freshly distilled and sterilized water 
which is to be utilized for the injection should be run into the 
solution cylinder. The quantity of water differs with the amount 
of neosalvarsan to be utilized. This table will set forth the proper 
amounts : 

For Dosage I (0.15) use 25 c. c. 

" " 11(0.3) " 50 c. c. 

" " IIK0.45) " 75 c.c. 

IV (0.6) " 100 c. c. 

" " V(o. 75 ) " 125 c. c. 

" VI (0.9) " 150 c.c. 

This water must be room temperature and never hot, as hot 
water is likely to produce oxidation and give rise to reactions. 



70 THE TREATMENT OF SYPHILIS 

The method of opening the neosalvarsan ampule is identical 
with that of salvarsan. The contents of the ampule should be 
scattered lightly over the surface of the water and the product 
will then very promptly go into solution. It is very seldom one 
finds occasion to agitate this solution, even in the slightest de- 
gree. 

The neosalvarsan solution is then filtered into the cylinder 
which is to be utilized for that purpose, and the freshly distilled 
and sterilized water as it is used in the administration of salvar- 
san should be placed in the other cylinder. 

The technic for removal of the air and for preparing for the 
injection is identical with that already given for salvarsan, and 
practically every point brought out in the chapter on salvarsan 
can be duplicated in this connection. 

The Concentrated Intravenous Administration of Neoarsphena- 

rnine 

One of the reasons for the widespread popularity of neo- 
arsphenamine is the ability of the physician to administer it in 
concentrated solution. The amount of fluid to be used seems 
to be a matter of opinion. Some employ only 10 c. c. of water in 
giving 0.9 gram neosalvarsan and others employ solutions up to 
50 c. c. The favorite quantity of solution is about 25 c. c. 

Two reasons are advanced for the use of the concentrated 
solution. The first, and doubtless the most general, is that it is 
"the lazy man's method." Some believe that as the necessary 
preparation for the injection is reduced to a minimum, such a 
small amount can be hurriedly injected. 

The second reason is that some physicians hesitate to intro- 
duce a large and what they deem an unnecessary quantity of 
fluid into the circulation. 

In the first instance it is doubtless true that there are prac- 
titioners who employ neosalvarsan on account of its ease of 
preparation. For some reason they feel that the addition of 
sodium hydroxid to the salvarsan solution requires a degree of 
skill or patience which they do not care to exercise. Again, some 
men are inclined to the newer product on account of the small 



TECHNIC OF NEOARSPHENAMINE ADMINISTRATION 71 

amount of apparatus required for the injection. With others, 
time seems to be the deciding factor. They begrudge the few- 
extra minutes demanded by the use of the gravity apparatus and 
consequently seek the quicker and more convenient way of 
utilizing the services of a Luer syringe. 

Reasoning of this nature is entirely wrong. The matter of 
time should not enter into the practice of medicine, especially 
when so grave a disease as lues is the enemy to be combatted. 
"The best is none too good" for the patient, and only the best 
method of giving a remedial agent should be considered. 

The relative value of salvarsan and neosalvarsan is con- 
sidered elsewhere and is not germane to the subject now under 
discussion, but we do most emphatically protest against the 
use of neosalvarsan or any other drug merely because it is easy 
of application. 

Time an Important Factor for Safety 

If upon due reflection and study of existing conditions the 
physician determines upon the use of neosalvarsan, he should 
bear in mind the strictures placed upon the rapid injection of the 
drug by Dr. George W. McCoy, U. S. P. H. S., and discussed at 
length in another chapter. He believes and rightfully, we feel, 
that two minutes should be given to the injection of each deci- 
gram of arsphenamine or twelve minutes to each maximum dose 
of 0.6 gram. As one and one-half decigrams of neoarsphenamine 
are equivalent to one decigram of arsphenamine, the natural 
assumption is that Dr. McCoy believes twelve minutes should 
be consumed in the injection of 0.9 gram neoarsphenamine. 

If his sensible and necessary injunctions are carried out the 
time factor will not enter into the consideration of the use of con- 
centrated solutions of neosalvarsan. 

Of the ease of preparation, owing to a lessened amount of 
apparatus, nothing need be said, for the fact remains that the 
method offers great convenience in this particular connection and 
we are heartily in sympathy with those who employ it on that 
account. 



72 THE TREATMENT OF SYPHILIS 

The second reason, i. e., the amount of water put into the cir- 
culation, opens up a question concerning which there has been 
much discussion. Each school has arguments which appear 
to offer conclusive proof that it is correct in its deductions. We 
must admit with real frankness that long usage of both methods 
has not convinced us that either is wrong. 

We formerly employed 300 c. c. in administering 0.6 gram 
salvarsan. No untoward effects were observed from the use of so 
much fluid. Later, the amount was reduced to 250 c. c. and 
finally to 180, or 30 c. c. per decigram, and we have no present 
expectation of going below this amount in the administration of 
arsphenamine solutions. 

It must be admitted that in a few unguarded moments, sal- 
varsan has been injected by us for experimental purposes, in a 
concentration as low as 7 c. c. per decigram. Grave fears followed 
the use of this low concentration, and the patients were carefully 
observed for unpleasant symptoms, which, however, happily 
did not ensue. 

One swallow does not make a summer, but the experience has 
not been repeated lest some of the reactions we read about might 
fall to our lot. 

In the use of neosalvarsan we formerly used the gravity 
method, giving every decigram of neosalvarsan in 20 c. c. or 
180 c. c. for a full dose. Added experience caused the amount to 
be lessened from time to time. When the use of a dilute solution 
of neosalvarsan is believed to be preferable, from 100 to 130 c. c. 
is deemed the proper amount. If it is felt the patient can or 
should have a smaller amount of water, a concentration ranging 
from 20 to 50 c. c. is given. Full blooded persons are generally 
picked for the greater concentration. As a rule, all things being 
equal, 25 c. c. is the average amount of fluid utilized. 

Danger of too Concentrated a Solution 

At the instigation of a colleague, who enthusiastically related 
marvelous serological results following 0.9 gram neosalvarsan in 
10 c. c. of water, this method was employed for several injections 



TECHNIC OF NEOARSPHENAMINE ADMINISTRATION 73 

on four patients, all men in good general condition. After the 
injections each man complained that "the medicine is awfully 
strong," or " that shot had too much kick" or otherwise expressed 
his disapprobation of the method, not knowing of the undue 
concentration. They experienced dizziness and in some instances 
nausea, and one man felt an unpleasant tingling of the fingers. 
As these men had received three or more injections in concen- 
trations of 25 c. c. or greater, it was deemed advisable to abandon 
the use of the more concentrated solutions. It is worthy of note 
that the subsequent use of the usual concentration elicited no 
complaint from these patients, nor did they exhibit further 
dizziness, nausea, or other symptoms, during the remainder of 
their course of treatment. 

It is hardly necessary to give an abundance of evidence as to 
the value of the concentrated method, on account of its wide 
usage. It may not be amiss, however, to quote the experience of 
Favre and Massia {Press medicale) who successfully gave 3,150 
injections in an average of 18 c. c. of water each. They employed 
a very fine needle, were able to enter small veins, and found 
that this high concentration showed no evidences of vein irrita- 
tion. Reactions were few and very mild in character. They be- 
lieve that the use of mercury with neosalvarsan lessens the prob- 
ability of reactions. 

We urgently advise the use of mercury with salvarsan and 
neosalvarsan in all cases where tolerated, not so much for its 
anti-anaphylactic as for its anti-luetic action. 

Technic of Concentrated Method 

In the utilization of this method, the patient is prepared as for 
the dilute injection of either salvarsan or neosalvarsan and, in- 
stead of using the apparatus for the dilute injection, a Luer 
syringe of from 25 to 50 c. c. capacity takes the place of the 
double glass cylinders, with the bracket, rubber tubing and 
three-way stopcock. The solution is made in a wide-mouthed 
glass graduate instead of in a tall, glass cylinder. 

After the ampule has been sufficiently immersed in alcohol, 
it is opened and the contents sprinkled on the surface of the 



74 THE TREATMENT OF SYPHILIS 

freshly distilled water in the graduate. The amount of water 
depends on the ideas of the physician. Our practice is as a rule 
to give it in about 25 c. c. The neosalvarsan very speedily goes 
into solution. As the solution should be filtered, another glass 
graduate can be utilized for this purpose. As soon as this has 
been completed, the solution is drawn into the sterilized Luer 
syringe. The needle is then introduced. When the operator is 
certain that the needle is squarely within the vein, as indicated 
by the backward spurting of the blood, the syringe is attached 
to the needle and the contents very slowly injected. The same 
length of time should be consumed in administering the con- 
centrated solution as in the dilute. This means that the operator 
must push the piston of his syringe so slowly as to be almost 
imperceptible. 

The amount of time which Dr. McCoy recommends — twelve 
minutes for the full dose — shows that in giving a 25 c.c. con- 
centration not over 2 c.c. should be injected a minute. 

Subcutaneous Injection of Neoarsphenamine 

Neoarsphenamine can be injected subcutaneously without 
difficulty provided the operator has a very careful technic. The 
great desideratum is not to put it into the fatty tissues, into the 
fascia or into the muscles. 

One of the firmest advocates of the subcutaneous administra- 
tion of neosalvarsan is Dr. Joseph A. Thomas of Valdosta, Ga. 
He has used this method for six years, has given a very large 
number of injections in this manner and regards it very highly 
indeed. The preparation of the patient is looked upon as a very 
sacred trust by Dr. Thomas. He pays especial attention to the 
gastro-intestinal tract and insists that the diet on the day of 
administration be exceedingly simple and he particularly em- 
phasizes that no tomatoes should be ingested, as he has had 
cases of vomiting where this article of food has been taken, but 
he has never seen vomiting from any other cause. 

He is also particular about testing the secretions of the mouth. 
If he finds an acid condition he utilizes alkalis until the system 






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TECHNIC OF NEOARSPHENAMINE ADMINISTRATION 75 

becomes practically free from acidity. He believes this to be 
essential for the prevention of unpleasant after-effects, although 
in a letter to the author he says that he has not yet had any 
reactions. 

Dr. Thomas then examines the patient carefully for indications 
as to renal, cardiac or neurological disturbances. Those caused by 
syphilis do not form contraindications to the drug but, if present 
from other causes, he treats the cause before going further with 
neosalvarsan administration. 

Dr. Thomas* Technic 

For the employment of neosalvarsan subcutaneously, Dr. 
Thomas utilizes (1) a 10 c. c. Luer syringe with a 20 gauge 
platinum needle; (2) a syringe with a small needle for the local 
anesthetic; (3) a glass graduate which will hold 20 c. c; and 
(4) freshly distilled, sterilized water. 

After the ampule of neosalvarsan has been thoroughly sterilized 
by immersion in alcohol, he opens it and dissolves the contents 
of the ampule in 10 c. c. of freshly distilled water at room tempera- 
ture. 

The patient is placed upon his abdomen and the skin at the 
angle of the scapula is painted with iodin around the point an 
inch or two in circumference. It is then anesthetized with a 
few drops of cocain. The neosalvarsan solution is drawn up 
into the Luer syringe and is injected UNDER the skin and not 
in it or in the fascia but in the connective tissue between the 
skin and the fascia. Dr. Thomas lays particular stress upon the 
importance of this point. 

The injection should be given very slowly. He advises that the 
operator make certain the needle is free and not in the skin by 
gently moving the needle from side to side. Upon the completion 
of the injection the site should be massaged thoroughly, so that 
there may be a wide-spread distribution of the solution under 
the skin. This massage prevents the formation of a lump. The 
point of entrance of the needle is covered with sterile gauze and 
adhesive. 



76 THE TREATMENT OF SYPHILIS 

Dr. Thomas says that very little pain follows this method of 
administration and when it is observed the pain will practically 
always be found to be intercostal and largely referred to the 
anterior aspect of the chest. The patients feel as if they had a 
pain over the heart, but the pain in Dr. Thomas' opinion, is of 
small consequence and it has been very seldom necessary for 
him to administer an opiate. 

The advantage of the subcutaneous administration of neosal- 
varsan over other methods is that it is unusually simple, is with- 
out danger, gives at least as good results as the others, and there 
is practically no after-pain and no detention from business. 
Dr. Thomas believes that the action of the drug is prolonged for 
about two weeks. He has injected several hundred patients in 
this manner and has never had any serious after-effects and 
only one of his patients has been compelled to go to bed. In 
this instance the temperature went to 105 F. This patient was 
in his secondaries with a malignant infection and the medical 
attendant feels that the cause of the rise in temperature was due 
to the liberation of many endotoxins following the administra- 
tion of the spirochetecide. 




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CHAPTER IX 

THE METHODS OF EMPLOYING THE MERCURIALS AND IODIDES 

The Intramuscular Method of Injecting Mercury 

The intramuscular injection of the soluble or insoluble forms 
of mercury requires considerable care and should not be re- 
garded lightly. 

The favorite site for injection is about one inch from the 
crease of each buttock and the parts must be sterilized, prefera- 
bly with tincture of iodin. 

Platinum needles of 20 gauge are best adapted for this work, 
especially when soluble preparations are being used. The 
needles should be two inches long, so that the mercury can be 
deposited in the muscle and not in the fat or subcutaneous tissue. 
Careful examination of the needle should be made before each 
injection to ascertain any structural weakness. If a needle is 
broken off in the gluteal region the parts must immediately be 
laid wide open and the part extracted, for needles in that section 
of the body are rapid travelers. 

The needle must be thoroughly sterilized before use and after 
the injection the bore must be cleared of the detritus, lest some 
may be left in the bore and, having partially decomposed, be 
injected into the body at the time it is next employed. 

When any form of mercury is to be injected, we strongly 
recommend an all glass, 2 c. c. Luer syringe. 

In carrying out the operation of injection, after the site has 
been sterilized, we plunge the needle, minus the syringe, deeply 
into the muscle, with one short stab. This method causes the 
patient much less pain than slow penetration. 

If blood comes out of the shank of the needle, it should imme- 
diately be withdrawn, as a vessel has been entered. We have 
seen patients collapse after an injection of mercury when the 



78 THE TREATMENT OF SYPHILIS 

syringe was attached to the needle and no precaution against the 
entrance of a blood vessel observed. 

If blood does not follow the introduction of the needle, the 
syringe should be attached and the contents of the barrel slowly 
injected. 

We heartily condemn undue haste in making these injections 
as we believe much of the soreness following this form of medica- 
tion is due to too rapid introduction. 

After the mercury has been deposited in the muscle, the needle 
is withdrawn and the part slowly and thoroughly massaged under 
a piece of gauze. This acts to prevent the lumps which appear 
following gluteal injections, forming the so-called "cobble- 
stone " buttocks. 

As soon as bleeding stops, the point of entrance is sealed with 
collodion to prevent possible infection. 

The Inunction Method 

Many physicians believe the inunction method is the best, 
especially if the rubbing can be done by a person experienced in 
such work. This method has the advantages of causing no pain, 
of promptly and thoroughly saturating the body with the drug, 
and of non-interference with the digestive tract. Inunction is 
quite necessary in persons who are old or debilitated, or very fat, 
and in pregnant women, as these types cannot stand injections. 

The inunction has an added advantage in that it is stored up 
in the follicles of the skin and is eliminated through the urine 
long after the rubbings have been discontinued. 

The old-fashioned unguentum hydrargyrum is often used, but 
we prefer an ointment made as herein set forth, as it leaves no 
trace on the skin and is not unpleasant in odor: 

ioo parts of mercury are mixed with 15 parts of anhydrous 
lanolin and 3 parts of olive oil. Carefully stir, adding the mer- 
cury in small quantities, but only when no more mercury pellets 
are visible. Then add a nearly cold mixture of 112 parts of lard 
and 70 parts of mutton tallow, this latter mixture having been 
prepared by melting together, and mix the whole carefully. The 



THE MERCURIALS AND IODIDES 79 

resultant salve is of bluish-gray color and no mercury pellets 
should be visible to the naked eye. 

Anatomical Sites for Inunctions 

We suggest, if possible, inunctions just before retiring on seven 
successive days on these anatomical locations: 

1 st day — Right and left calves. 

2nd " Right thigh. 

3rd " Left thigh. 

4th " Abdomen. 

5th " Chest. 

6th " Right arm and forearm. 

7th " Left arm and forearm. 

The rubbing should be continued for twenty minutes or until 
all the mercury has disappeared. 

After the inunction on the seventh day, the patient should 
take a hot, soapy bath and the following day commence another 
seven day series. 

The patient should wear woolen undergarments and change 
them only after the seventh day bath. 

The inunctions are continued as long as the case demands and 
each case must be individualized. 

Administration by the Mouth 

We mention this method only to condemn it and believe the 
physicians who pursue this line of treatment are following an 
ignis fatuus. 

Many a case of tabes and paresis has followed the use of mer- 
cury per os, the patients meantime being sublimely unconscious 
of their ultimate fate. 

Continued use of mercury by this means impairs the power of 
the alimentary tract to absorb it and anemia, diarrhea and gen- 
eral debility often follow its continued use. 

Fumigation and Inhalation 

These methods are recommended when there are extensive 
ulcerating lesions, involving the deeper structures but are not 



80 THE TREATMENT OF SYPHILIS 

suggested for ordinary cases. When indicated, however, these 
means are of real value. 

Intravenous Method 

This is not yet sufficiently perfected to permit of discussion of 
a helpful nature. We doubt not that eventually the intravenous 
route will form one of the standard methods. 

Form of Mercury to be Used 

The question arises as to whether one will use a soluble or in- 
soluble form of mercury. The insoluble in the form of the salicy- 
late is very popular, although, both calomel and gray oil have 
their ardent advocates. For example, Dr. J. A. Fordyce, if he em- 
ploys an insoluble form, utilizes gray oil " in the form of mercurial 
cream, of which 5 minims represent 1 grain, in a series of ten or 
twelve injections, or salicylate of mercury 40 per cent suspension 
in doses of 1 to 3 grains, gradually increased, ten to twelve in- 
jections constituting a course." 

We have utilized this form of treatment with results not en- 
tirely satisfactory. Our dissatisfaction was largely due to the 
soreness which was likely to follow the injections and particularly 
to the formation of lumps in the buttocks, the "cobble-stone" 
buttocks, in which condition mercury was found to be unab- 
sorbed, sometimes weeks after the original injection. 

We thereupon experimented with the succinimid, which is a 
soluble product. This was found to work well in clinics where the 
patients were men used to very heavy work and who were not 
easily affected or disturbed by localized soreness, but in private 
practice it proved to be altogether too painful, nor did the benzo- 
ate work to our satisfaction. 

The soluble mercury of choice we have found to be the bi- 
chlorid, which we ordinarily administer in the beginning of 
treatment in J^ grain doses. If that is readily taken, the dose 
is increased to }/2 grain and then to 1 grain. 

Dr. Fordyce (Amer. Jour. Med. Sci., October, 1916) advised 
giving a soluble mercury intramuscularly every other day and 
quoted the bichlorid as his preference of the soluble forms, 




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THE MERCURIALS AND IODIDES 81 

giving from twenty to thirty injections either daily or every other 
day. 

A Convenient Means of Mercurial Administration 

One objection to the hypodermic use of mercury has hereto- 
fore been the frequent inability to obtain an absolutely certain 
dosage of mercury, especially where it has been put up in an oily 
suspension by the local pharmacist. Several years ago there 
came to our attention an ingenious method of holding insoluble 
or soluble mercurials in the form of collapsule hypo-fills, which 
consist of bulbs made of gelatin holding an exact amount of 
the mercurials. By means of these collapsules we carried on a 
long series of experiments utilizing the salicylate, calomel, suc- 
cinimid, benzoate and bichlorid. The mercurial is held in a base 
containing neutral vegetable anhydrous fats and when intro- 
duced into the body breaks down in the form of alkaline pal- 
mitates and glycerin. The bichlorid is readily absorbed, the 
injection is followed by practically no pain and the "cobble- 
stone" buttock is something unknown. 

The great advantage of the use of collapsules is that the physi- 
cian is certain of exact dosage and he is also given a most con- 
venient method of administration. Our experience has been that 
the use of mercury in this form seems to increase the body weight 
and the arsphenamine is very materially aided. 

From the cut given herewith it will be observed that the gelatin 
top of the collapsule is clipped off, and the contents squeezed 
into a 2 c. c. Luer syringe, which is warm from the previous 
sterilization, and it is, therefore, melted sufficiently to permit 
of immediate injection into the body. 

Advantages and Disadvantages of Soluble Mercury 

The great advantage of mercury in the treatment of syphilis 
is to have it as constantly in the system as possible. 

It might seem almost suicidal to advocate the use of bicholorid 
of mercury in from 34 to i grain doses. This, however, is the 
dosage which Fordyce has employed in his clinics for a long time 
without any difficulty, and we have also utilized it to the very 



82 THE TREATMENT OF SYPHILIS 

best advantage. It means, however, that the patient should come 
every other day for treatment and, while this can be accom- 
plished so far as the ordinary dispensary patient is concerned, it 
is often difficult for the private patient unless he be in a hospital. 

Another disadvantage of bichlorid is the possibility of a renal 
nephritis. We have never seen such a condition but the possibil- 
ity is ever present and must be most carefully considered. 

The use of bichlorid means that the urine must be constantly 
examined so that the condition of the kidneys can be at all times 
known to the physician. 

If the patient can come to the office every other day, or even 
twice a week, we recommend the bichlorid; if it is impossible 
and the patient can only be seen once a week, the salicylate is 
preferable. In some cases one grain of bichlorid injected once 
a week has been absorbed so slowly that we have been content 
to give weekly injections of one grain each. 

Iodides 

The employment of the iodides in the treatment of syphilis 
has undergone a very radical change since the introduction of 
salvarsan as an anti-luetic agent. It was formerly a part of the 
stock treatment of the syphilitic and after vigorous mercurial 
medication he was placed upon the iodides, preferably the iodid 
of potassium. Despite the fact that this drug disarranges the 
stomach of many patients, it was very generally utilized, al- 
though at times other preparations of iodin, such as salts of 
sodium, strontium, and ammonium, have been used. There 
are on the market a number of proprietary products containing 
iodides, which have been formulated in combinations, tending 
to eliminate the uncomfortable and unpleasant features caused 
by taking the raw iodides. 

Spirochete not Affected by Iodin 

We have learned, however, that iodin has little or no effect 
upon the spirochete. This was first brought to the attention 
of the profession by Colonel (then Captain) H. J. Nichols, U. S. 
Army {Journal of Experimental Medicine, p. 196, 191 1). 




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THE MERCURIALS AND IODIDES 83 

Clinical observation has demonstrated that the drug does not 
change the Wassermann reaction and it has practically no effect 
upon primary syphilitic lesions. The facts would seem to con- 
demn iodin as a drug for use in syphilis; however, it has a very 
definite place in the treatment of tertiary syphilis as well as in 
syphilis of the nervous system. The particular effect of the drug 
seems to show itself upon the gummata. Just how it works to 
produce this effect upon gummata is a discussed question, but 
the fact remains that in the conditions mentioned it is of value. 

Iodid of potassium can be used by the mouth or by hypoder- 
mic injection and some syphilologists have utilized it by in- 
travenous injection and also by enema. The most common 
method of oral administration is that of the saturated solution; 
100 grains of the potassium iodid are dissolved in sufficient water 
to make 100 drops. Each drop, therefore, contains 1 grain. It 
is usual to start the patient off with 10 drops one hour after 
each meal in a half glass of milk or water and to increase one 
drop at each dose or three drops a day until the patient shows 
signs of intolerance. By giving the drug an hour after each meal 
the potassium iodid finds a more ready reception in the stomach, 
because the starchy contents have been changed into sugar. 

Another method of administration is the formula of Ricord. 
He did more to popularize the drug in the treatment of syphilis 
than any other man. This formula is: 

Kali iodidi 4 . o 

Syrupi corticis aurantii 250.0 

M. Sig. One tablespoonful three times a day. 

If the drug is to be administered hypodermatically, from 4 to 8 
grains are given in 50 c. c. solution and any pain which may ac- 
company the injection can be corrected by the introduction of 
codein to the solution. 

We cannot speak of the intravenous use of potassium iodid 
as we have had no experience therewith. 

If the enema form of administration is used, the large bowel 
should be thoroughly cleansed with an ordinary enema; then it is 



84 THE TREATMENT OF SYPHILIS 

well to inject from i to 3 drams of potassium iodid in pepton- 
ized milk to which have been added 5 drops of laudanum. 

Only Heavy Doses of Iodides are Effective 

The great value of the iodides is observed in heavy doses. 
Many physicians are in the habit of prescribing 10 grains three 
times a day. There is no more advantage of putting this amount 
of iodid into the patient's stomach than into his shoe. If results 
are to be obtained, the drug must be administered in heroic 
doses. We have seen many cases in which from 100 to 125 
grains were administered three times daily. In these cases, par- 
ticularly those in which gummata were present, the results were 
a little short of marvelous, as the lesions would actually seem 
to fade away under this heavy dosage. 

One of the difficulties in taking the drug are the coryzal symp- 
toms which follow the administration of comparatively small 
amounts. This is due to the fact that the average dose seems to 
be excreted by means of the nasal mucous membrane. The large 
dosage is eliminated by the kidneys and causes little or no nasal 
complications. 

Potassium iodid in large doses is something of a heart de- 
pressant and it is urged that when patients are given these large 
amounts they be not permitted to carry on heavy physical work; 
they should be watched with considerable care. 

The amount of potassium iodid which the patient can absorb 
varies with the individual; some show signs of iodism after a very 
small amount of the drug. As about 80 per cent, is excreted 
daily there is an accumulation in the body from the daily dosage. 
Therefore, a heavy dose should be employed until the patient 
has reached his limit when the dose should be moderated. 

Iodism 

Iodism is first brought to the patient's attention by a metallic 
taste in the mouth or by a coryza, with sneezing and the other 
symptoms of a head cold. In some instances this coryza becomes 
somewhat severe, but it passes away by a diminution or a com- 
plete cessation of the drug for the time being. 




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THE MERCURIALS AND IODIDES 85 

The use of potassium iodid is very often attended with gastro- 
intestinal disturbances as well as dermatological lesions, such 
as iodid pimples, which are closely analogous to acne vulgaris. 

The physician should do everything in his power to prevent 
over-stepping the bounds of tolerance in the administration of 
this drug. It is well to have daily examinations of the urine 
made to observe the excretion of iodin. Dr. Loyd Thompson 
{Syphilis, p. 251, 1916) recommends mixing 2 c. c. each of urine 
and pure hydrochloric acid and adding a few drops of chloro- 
form. The presence of iodin is indicated by a pink coloration of 
the chloroform upon settling to the bottom of the tube, following 
its inversion two or three times. In the event that iodin is not 
discovered, the physician would do well to watch the case slowly 
lest iodism appear. 

Resume of the Treatment of Syphilis 

Examination of Patient. — Patient to be examined very care- 
fully to see if any contraindications to arsenical treatment be 
present. 

Urine to be examined before the injection. 

No food in the stomach for six hours before injection or four 
hours thereafter, and patient to rest in bed after the injection. 

Dosage of Arsphenamine or Neoarsphenamine 

Drug dissolved in room-temperature, freshly distilled, steril- 
ized water and injected very slowly. 

Initial dose for men 0.2 or 0.3 gram salvarsan or 0.3 or 0.45 
gram neosalvarsan; for women, 0.2 gram salvarsan or 0.3 gram 
neosalvarsan. 

Subsequent doses for men 0.4 to 0.6 gram salvarsan or 0.6 
to 0.9 gram neosalvarsan; for women, 0.4 or 0.5 gram salvarsan 
or 0.6 to 0.75 gram neosalvarsan. 

Mercury 

Soluble — bichlorid: from % to X A grain injected in the buttock 
three times a week, if possible. 



86 THE TREATMENT OF SYPHILIS 

Insoluble — salicylate: i grain injected into the buttock once 
a week. 

Urine should be examined at frequent intervals to ascertain 
the presence of any renal irritation caused by the mercury. 

Iodides 

Begin with 10 drops saturated solution three times a day in 
water or milk, increase so that the patient is taking from ioo 
to 125 grains three times a day when the occasion requires. 

Courses of Treatment 

Salvarsan or neosalvarsan to be given at from 5 to 7 day in- 
tervals until eight injections have been administered. Mercury 
to be administered for twelve weeks; three times a week in the 
soluble form, if possible, and once a week in the insoluble form. 

Iodides to be administered when syphilitic gummata are 
present, in latent syphilis, and in syphilis in which the nervous 
system is involved. 

After one course the patient to rest for four weeks and then a 
Wassermann taken. 

If positive, a second course is necessary and subsequent courses 
depend upon the condition of the Wassermann. 

If negative, a Wassermann to be taken at monthly intervals 
for a year, after which they should be taken at least quarterly 
over a long period. 

Before pronouncing a patient cured, there should also be a per- 
sistent negative Wassermann of the spinal fluid. 

General Treatment 

It must be remembered that syphilis is a constitutional 
disease and the patient is very likely to require other than anti- 
luetic treatment. On account of the destruction of the red blood 
corpuscles by the inroads of the disease, tonics are usually de- 
manded. For emaciation, cod liver oil is recommended; for 
anemia, iron; and, for the stimulation of general nutrition as 
well as the nervous system, strychnin is advised. Tincture of 




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THE MERCURIALS AND IODIDES 87 

nux vomica is also a tonic which works to advantage in syphilis, 
particularly when combined with tincture of cardamom comp. 
and glycerin. 

The patient's weight should be observed from time to time and 
the condition of the blood should also be watched by means of 
the hemoglobinometer. 

Many patients do well under a Turkish bath, without the cold 
plunge, once or twice a week. This aids in elimination and is of 
particular assistance in those cases in which the mercury may be 
slow in leaving the system. 

Hydrotherapeutic Treatment 

In addition to the hygienic treatment of the syphilitic as laid 
down in another chapter, the hydrotherapeutic form of treat- 
ment should not be overlooked when patients can afford such. 
The various hot springs of the country offer specific methods of 
hydrotherapy which are undoubtedly beneficial. Patients who 
are not able to go to hot springs for treatment of this nature are 
often benefited by the baths at such resorts as Saratoga Springs. 
There is nothing at Saratoga which can be claimed to possess 
curative properties, but patients who are sent there are given 
the eliminating treatment with carbonated baths at the Lincoln 
Bath House at temperatures varying from 97 to no°. In 
alternation with these baths, the electric cabinet baths with a 
fan spray following, for reaction, are employed. Very satisfac- 
tory results have been observed when this line of treatment has 
been carried out in conjunction with the usual anti-luetic treat- 
ment. 



CHAPTER X 

REACTIONS AND ACCIDENTS FOLLOWING THE USE OF 
ARSPHENAMINE 

Reactions 

Sometimes during an injection of arsphenamine or neoar- 
sphenamine certain phenomena will be noted which have been 
termed nitroid crises. These include nausea, malaise, flushing 
of the face, headache, precordial distress and dyspnea, and are 
usually inconsequential. Being of an anaphylactoid type, they 
can be relieved by the intramuscular injection of from ten to 
twenty minims of a 1:1000 solution of epinephrin. When pa- 
tients are known to exhibit such symptoms, difficulty can be 
obviated by the injection of the epinephrin ten minutes before 
the anticipated injection of salvarsan. 

Dr. J. H. Stokes of Rochester, Minn. (/. A. M. A., Jan. 25, 
19 19) observed that the epinephrin administers a shock to the 
system by its powerful vasomotor action and states that he has 
"seen occasions in which patients have for the moment seemed 
in as much risk of serious damage from the therapy as from the 
original arsphenamine reaction." 

Dr. Stokes thereupon set out to discover a method which 
should protect his patients against reactions following the use of 
arsphenamine and to support his view that such a reaction is a 
manifestation of anaphylactic shock. He sought, in other words, 
an anti-anaphylactic agent. For this purpose he utilized atropin, 
which has an inhibitory effect. 

It was first employed in the case of a woman whose intolerance 
to neoarsphenamine was beyond doubt. Suffering from a florid 
follicular secondary syphilid, the initial moderate dose was 
followed by a rather sharp Jarisch-Herxheimer reaction, and, 
during her first course of five injections, she gave abundant 
evidence of gradually increasing intolerance to the drug. 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 89 

Six weeks later the administration of 0.3 neoarsphenamine 
was followed in two minutes by an intense scarlet flush and 
edema of the face and neck, with cough, stridor and vomiting. 
A subcutaneous injection 10 minims of 1 :iooo of epinephrin re- 
stored her completely. 

A week later the woman was given 1/50 grain of atropin 
hypodermatically and fifteen minutes later received 0.6 neo- 
arsphenamine, with only a slight reaction, and at the period of 
the third injection the following week the use of atropin per- 
mitted the injection of 0.7 gram with only distinct nausea as a 
disagreeable factor. 

Successful Employment of Atropin 

At a later period, deciding to produce, if possible, antianaphy- 
laxis by atropin, Dr. Stokes gave the woman intravenously 
0.05 gm. of the drug in 0.5 c. c. of water. He goes on to say: 

"The neoarsphenamine used was of the same control number 
as that employed for the previous injection, which had shown 
itself capable of producing marked reaction in this patient 
(Control V U J). Following the injection of the half decigram 
dose, the patient became slightly dizzy and was a trifle nauseated 
on returning to bed. One hour after the preliminary injection 
the patient received 0.55 gm. of neoarsphenamine intravenously 
in concentrated solution, injected at the usual rate. The com- 
plete inhibition of all reaction was striking. There was no flush, 
no nausea nor vomiting, no dizziness, cough nor stridor. The 
eyes became slightly suffused. The patient felt so much better 
than usual as to astonish her and all those who knew of her re- 
actions. She was returned to her room, and no reaction was re- 
ported for twenty-four hours. At the end of this time, without 
rise of temperature or any other marked systemic symptoms, a 
generalized macular erythma of the typical late toxic type 
appeared. It was not accompanied by constitutional symptoms 
and disappeared two or three days later. It was judged wise, 
however, not to invite an exfoliative dermatitis by any further 
arsenotherapy." 



QO THE TREATMENT OF SYPHILIS 

Dr. Stokes comments further on the matter: 

"This case was surrounded by all the precautions against 
pseudoreaction that we could devise. The reactions observed 
were typical of the acute nitritoid crisis and we felt that the 
sequence of events, as described, had not been modified by 
presuppositions on the part of the patient or by hysterical man- 
ifestations. Abundant objective evidence of the patient's in- 
tolerance was available. Not the least interesting suggestion 
based on these observations is the possibility that the acute 
anaphylaxis and the delayed toxic erythema are different types 
of reaction. An antianaphylaxis which was developed to protect 
the patient against the former failed to protect against the latter 
complication. The influence of atropin seemed to be quite 
definitely a function of the dosage, and doses below 1/50 grain 
failed to protect the patient against shock. 

" Since its successful employment in the case described, we 
have resorted a number of times to the induction of antianaphy- 
laxis as a protection against acute arsphenamine reaction, notably 
in the treatment of patients with tuberculids, who show an 
idiosyncrasy in about 50 per cent of the cases. I have noted 
with interest Danysz' impression, which my experience confirms, 
that small preliminary injections ' vaccinate ' the susceptible 
patient, so to speak, against the larger doses, an observation 
which Danysz supports by animal experiment, and offers likewise 
as a rationale for the regulation of dosage in treatment, and a 
means for increasing individual tolerance of the drug." 

Summary of Stokes* Conclusions 

"The acute 'nitritoid' crisis or reaction to arsphenamine is a 
form of anaphylactic shock, explainable on physicochemical 
grounds as the result of a precipitation either of the drug from 
its colloidal solution, or of the colloids of the blood plasma, by 
the drug, or by an impurity. The reaction following the injection 
of an acid or only partially alkalinized solution of arsphenamine 
either too rapidly or in too high concentration is presumably of 
the same type. 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 91 

"The nitritoid crisis can apparently be inhibited by a previous 
injection of atropin (1/50 grain), which further suggests that the 
reaction is a form of anaphylactic shock. 

"The induction of antianaphylaxis as described above further 
supports the belief that the nitritoid crisis is a form of anaphylac- 
tic shock. 

"The induction of antianaphylaxis in patients exhibiting per- 
sistent idiosyncrasy to arsphenamine or neoarsphenamine has 
proved clinically useful, and, as a means of increasing their 
tolerance of the drug, deserves further trial and study." 

Reactions from Faulty Technic 

In a very small percentage of cases a temperature may be 
noted, sometimes running as high as 103 . This may or may not 
be accompanied by pain, nausea, vomiting and purging. These 
cases were especially prevalent several years ago when too little 
attention was paid to the gastro-intestinal tract and to the fresh- 
ness of the distilled water and the sodium hydroxid. 

Rest in bed, pyramidon, acetyl-salicylic acid and liquid diet 
will promptly restore these cases. 

Care should be observed in subsequent administrations, the 
dose should be smaller and these patients should be given atropin, 
following the ideas of Stokes, as hereinbefore set forth. Epine- 
phrin given hypodermically will usually control the unpleasant 
after-effects of acute reactions. 

Some Late Reactions 

Among the late reactions are dermatitis and erythema, some- 
times accompanied by renal disturbance. A nephritis may also 
occur without any of the noticable dermatological conditions. 

Icterus occasionally follows the administration of arsphena- 
mine. Much trouble was experienced in France with the French 
arsphenamine and so much jaundice occurred in England during 
the war that special studies have been undertaken to locate the 
cause and determine a cure. 

Whenever chemicals containing ring compounds reach the 



92 THE TREATMENT OF SYPHILIS 

blood stream, certain decompositions take place yielding com- 
pounds of simpler structure which in turn cause a marked in- 
creased destruction of red blood corpuscles. These changes take 
place in from two to twelve hours and they in turn change the 
bile secretion, due to the clogging of the fine bile ducts and fol- 
lowed by inflammatory and hemorrhagic conditions. 

This happens when there is a hemolysis in the blood stream 
and this is one of the objections to the use of concentrated ar- 
senical solutions. In addition dermatitis exfoliativa may follow 
the use of the concentrated solution. Dr. C. N. Myers, U. S. 
Public Health Service, has demonstrated this last statement in 
about 1,000 cases, using the same material for the more dilute 
solutions as well as for the concentrated solutions. The der- 
matitis occurred frequently with the concentrated solutions and 
not a single case in the more dilute. 

The Herxheimer Reaction 

Another very rare symptom is the Herxheimer reaction. The 
liberation of endotoxins may cause symptoms of pressure, or 
some impairment of function. The Herxheimer is ordinarily 
noticed in connection with beginning brain lesions, although re- 
actions of a similar nature occur when lesions of the circulatory 
system or of the viscera are present. 

Great care should be exercised in the use of arsphenamine in 
cases such as described, and it is well to employ mercury or the 
iodides freely and for several days before the administration of 
salvarsan. Careful physical examination will guard against 
trouble in this connection. 

Nerve Disturbances 

Other so-called reactions are disturbances of the ocular, 
auditory and other nerves. These are generally indications of 
the activities of the syphilitic lesions and demonstrate the neces- 
sity for further arsenical treatment. For example, Benario ob- 
served an involvement of the auditory nerve in 62 cases out of 
14,000 treated by him with salvarsan. The deafness was tern- 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 93 

porary and disappeared as soon as the antisyphilitic treatment 
was discontinued. 

Jacobsen (Ugesk. for Lager, Copenhagen, March 13, 1919) 
discusses four cases of syphilis in the auditory nerve or labyrinth 
in which sudden deafness, ear noises or vertigo and vomiting were 
the symptoms of reaction, showing that lues had invaded the 
ear or that the drugs had caused a reaction. He says (/. A . M. 
A., May 10, 19 19) "analysis of these and similar cases on record 
seems to show that part of the neurorecurrences are due to a 
Herxheimer reaction to arsphenamine. This reaction congestion 
in a nerve confined in a narrow passage through bone injures the 
nerve and may cause permanent trouble. But the majority of 
cases of disturbances in the auditory nerve are the result of 
actual damage from the syphilis, combined with or possibly 
secondary to a syphilitic meningitis. There may possibly be also 
a small contingent of cases in which the nerve is suffering from a 
direct toxic action from the arsphenamine. Even in persons 
with normal ears, special care should be exercised in giving 
arsphenamine; during the exanthem stage or a little before this, 
it is wiser to give the arsphenamine^ only in combination with 
mercury." 

Very occasional symptoms, which are designated under the 
anaphylactic group, are coryza, sore throat, urticaria, indigestion 
and diarrhea, but they are as fleeting as they are uncommon. 

The Causes of Reactions 

Without doubt, there are numerous causes for reactions. 

Wassermann blames the bacterial proteins in the water; 
Wechselmann, the rapid dissolution of great quantities of spi- 
rochetes and the freeing of their constituent parts. Some ascribe 
reactions to the "setting free of some toxic substances from the 
spirochete," or to the "liberation of endotoxins from the killed 
organisms," or to impurities in the drug itself. 

Without doubt, each reason is tenable and reactions might be 
caused even by two of the reasons ascribed acting simultaneously. 
We are convinced, however, after a large experience in the ad- 
ministration of arsphenamine, that the febrile and gastro- 



94 THE TREATMENT OF SYPHILIS 

intestinal disturbances which may follow the injection will be 
found due to one or more of these causes : 

(a) Dissolving the arsphenamine in warm or in hot water. 

(b) Failure to use fresh double distilled water. 

(c) Too hurried introduction of the solution into the circulation. 

(d) Failure to dissolve thoroughly the arsphenamine in water 
before adding the salt solution. 

(e) Adding the sodium hydroxid solution after the salt solu- 
tion has been mixed with the arsphenamine solution, instead of 
before, thus producing a turbid solution. 

(f) Failure to use the sodium hydroxid in the proper propor- 
tions and manner. 

(g) Failure to filter the completed mixture before using. 

(h) Using gauze for filtering purposes that contains shreds 
which pass through with the mixture. 

(i) The use of impure chemicals. 

(j) Failure to prove that the arsphenamine solution was 
sufficiently alkaline. 

(k) A cracked ampule, permitting the access of air and a 
consequent oxidation of the drug. 

(1) Unclean apparatus. 

(m) Piercing the wall of the vein on the side opposite to the 
needle's point of entrance, thus infiltrating the tissues with the 
mixture, and causing local disturbances. 

(n) Using an excessive dose, or too frequent administration of 
large doses. 

(o) Too long delay after preparation in using the mixture. 

(p) Idiosyncrasy of the patient against arsenic preparations. 

(q) Non-recognition of the physical condition of the patient, 
who may have had a disease or diseases which contraindicate 
the uses of arsenic compounds. 

Summarized, imperfections in the technic of the operator or 
his failure to prepare properly his patient for treatment with 
arsphenamine. 

Undue Caution may be Harmful to Patient 
Many physicians are unduly cautious regarding the so-called 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 95 

reactions occurring during salvarsan injections, and interpret 
minor symptoms so seriously that the patient is oftentimes 
needlessly denied the benefit of arsphenamine treatment because 
of the over-anxiety of the administrator. 

We have seen physicians stop an injection the moment a 
slight flushing of the conjunctiva was observed. In some in- 
stances flushing is premonitory of trouble, but generally such a 
sign possesses no significance. 

If the operator will watch the heart through the pulse he will 
have an excellent guide to his further procedure. 

In initial cases the pulse may go to 100 or even higher owing 
to the nervousness of the patient and the sting from the intro- 
duction of the needle, but when the patient is reassured it shortly 
resumes its normal rate. In a recent series of 100 cases with one 
or more injections there was practically no variation in the pulse 
rate sufficient to cause the slightest unrest on the part of the 
physician. 

The Importance of Heavy Dilutions and Slow Injections 

We have urged for several years in our writings on syphilis 
and its treatment by salvarsan and mercury, that the technic 
of preparation and administration as laid down by the discoverer 
of the drug should be employed. 

Unfortunately too many physicians have attempted to im- 
prove on the technic, with the result that the patient is ofttimes 
the sufferer. 

We have laid especial emphasis on heavy dilutions and the 
necessity for slowness of entrance of the well-diluted drug into 
the circulation. We have also strongly advised the immersion 
of the salvarsan ampules in 95 per cent alcohol, so that any 
minute crack in the glass may be detected. Cracks hardly 
visable to the naked eye permit oxidation, and if undiscovered, 
cause consequent reactions. Many physicians have immersed 
the ampules in water, but the size of water molecules is too great 
to permit of entrance through very minute cracks. 

It is a pleasure, therefore, to observe that the United States 
Public Health Service, through the capable director of its Hy- 



96 THE TREATMENT OF SYPHILIS 

gienic Laboratory in Washington, Dr. George W. McCoy, has 
publicly directed attention to the absolute necessity of carrying 
out these important details. He makes a statement which many 
of us have believed and preached for years, that "any physician 
who fails to observe these precautions should be considered as 
directly responsible for serious results that follow the improper 
use of the drug." 

U. S. Public Health Service on Concentration and Rapidity of 

Administration 

A few feeble voices in the wilderness avail little, but a voice 
speaking with authority is clearly heard over the clamorous tu- 
mults of the multitude. The profession has every reason to con- 
gratulate itself that Dr. McCoy has directed the attention of 
arsphenamine users, present and prospective, to the absolute 
imperativeness of careful and proper technic, and, unless all 
signs fail, it will not be long before the reactions following ar- 
sphenamine injections will be but a memory. 

Dr. McCoy made known his dictum through a letter published 
in the weekly medical journals of May 10, 1919, which reads: 

"It appears that there is a lamentable want of care on the part 
of many physicians who administer arsphenamine as to the con- 
centration of the drug used and the time required for adminis- 
tration. 

"The Hygienic Laboratory receives many complaints in 
regard to untoward results from the administration of arsphen- 
amine made by various American producers. When careful 
investigation is made it is almost invariably found that the drug 
has been used in a solution that is too concentrated, and that 
it has been administered too rapidly. We have reports of a 
dose of 0.4 gm. being given in a volume of as little as 25 c. c. 
and injected within thirty seconds. Such practice is abuse, not 
use, of a powerful therapeutic agent. 

"If, in addition to the usual precautions as to the use of perfect 
ampules and neutralization, physicians would give the drug in 
concentration of not more than 0.1 gm. to 30 c. c. of fluid and 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 97 

allow a minimum of two minutes for the intravenous injection 
of each 0.1 gm. of the drug (in 30 c. c. of solution) the number 
of reactions would be very materially reduced. This would neces- 
sitate from 30 to 180 c. c. of the solution for the doses usually 
given and would require from six to twelve minutes for the in- 
jection. 

"Any physician who fails to observe these precautions should 
be considered as directly responsible for serious results that 
follow the improper use of the drug." 

The Journal of the American Medical Association, under the 
caption "The Administration of Arsphenamine," had this to 
say editorially (p. 1372): 

"Elsewhere in this issue appears a letter from Dr. George W. 
McCoy, director of the hygienic laboratory of the United States 
Public Health Service, concerning two special points in the ad- 
ministration of arsphenamine, namely, the dilution and the 
rapidity of administration. His letter is followed by a circular 
issued by the Public Health Service to all its officers covering 
the same general subject. Numerous disagreeable results fol- 
lowing the use of the various preparations of arsphenamine 
have led research workers to make a special study of the cause 
of these accidents. Such studies have indicated that most of the 
disagreeable results are not inherent in the preparations them- 
selves, but are produced through faulty steps in the adminis- 
tration of the remedies. The suggestions made in the circular 
of the Public Health Service, if followed by physicians, will aid 
in preventing repetition of disagreeable after effects." 

The Journal appends this note to Dr. McCoy's letter: 

"The United States Public Health Service has issued a cir- 
cular to its officers concerning the proper mode of administering 
these preparations. It is appropriate to reproduce this circular 
in connection with the letter of Dr. McCoy. Careful attention 
to the letter and the following points from the circular men- 
tioned will undoubtedly reduce the number of reactions following 
the use of arsphenamine preparations." 



9 8 THE TREATMENT OF SYPHILIS 

The circular issued by the United States Public Health Serv- 
ice to its surgeons is presented herewith: 

ADMINISTRATION OF ARSPHENAMINE AND NEO- 
ARSPHENAMINE 

TREASURY DEPARTMENT 

Bureau of the 

United States Public Health Service 

Washington, April 28, 1919. 
Bureau Circular 
Letter No. 163. 

Medical Officers, U. S. Public Health Service, 
and others concerned: 

In view of the variations of technique of the administration of arsphen- 
amine and neo-arsphenamine at various Service clinics, attention is invited 
to the following points, careful observation of which should reduce the 
number of reactions from the use of this drug. 

The ampule, before opening, should be immersed in 95% alcohol for 
fifteen minutes, so as to detect any crack or aperture not primarily recog- 
nizable. (Should such a breach be discovered, the contents of the ampule 
should be discarded.) 

ARSPHENAMINE 

(1) Solution: Cold, boiled, freshly distilled water should be used in all 
cases except in the case of "arsenobenzol" made by the Dermatological 
Research Laboratory, in which case hot water is required. No more solu- 
tion should be prepared at one time than can be given in 30 minutes. 

(2) Neutralization and alkalinization of the above solution: With a 
graduated pipette or burette add 0.9 cc. of Normal NaOH for each 0.1 
gm. of the drug (i. e., 5.4 cc. for each 0.6 gm.). The alkali should be added 
all at once and should quickly convert the acid salt solution of arsphenamine 
into the alkaline salt solution, or the disodium of salt of the arsphenamine 
base. The solution of arsenobenzol, which is hot, should be cooled before 
adding the alkali. This represents slightly more alkali than just enough to 
re-dissolve the precipitate formed by the addition of this reagent. 

The alkali used should be standardized against normal acid. Normal 
NaOH is a 4% solution of the c. p. product. However, if made on the basis 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 99 

of weight, it may be considerably less than this strength, hence the necessity 
for titration. It could be made up in amount sufficient for a month's use, 
if kept in a well-stoppered bottle and exposed to the air for only a few 
seconds at a time when using the solution. It should be kept in a bottle 
that has been used for NaOH solution for some time so that all action it 
might cause on the glass has already occurred. Where it is impossible to 
have this made up at the station, it will be furnished upon request from the 
Hygienic Laboratory. Should the NaOH solution become cloudy or con- 
tain a precipitate, it should be discarded. 

(3) Concentration of the Drug: It is desired to emphasize the fact that 
the concentration of the drug should not be greater than 0.1 gm. to 30 cc. 
of final solution. The practice of using concentrated solution is not only 
in direct conflict with the instructions on the circular, but carries a distinct 
hazard to the patient. 

(4) Method of Injection: The gravity method only should be used. 
Where several patients are to be injected from the same solution, the con- 
tainer of the solution should be graduated. If not already graduated, this 
can be done in a few minutes by sticking on a strip of adhesive plaster and 
marking the graduations on this. A convenient way to do this is to have 
each mark represent 30 cc. with a long mark for each 180 cc; then, if the 
volume is made up so that each 0.1 gm. of drug is contained in each 30 cc, 
the doses can be given accurately. It is a great convenience to have a 
glass stop-cock near the glass tubing which serves as a window just above 
the needle in order to control the rate of injection. If no stopcocks are at 
hand, the rate can be controlled by the size of the needle and the height of 
the column of fluid. A No. 18 or 20 B. & S. gauge is the best size needle. 

(5) Rate of injection: Operators should pay particular attention to the 
rate of administration and in no case exceed 0.1 gm. of drug (30 cc. of solu- 
tion) in 2 minutes. This point is especially emphasized because it is be- 
lieved that excessive rapidity of administration accounts for more unfavor- 
able results in the use of arsphenamine than any other one thing. 

NEO-ARSPHENAMINE 

The principal precautions to be observed in the administration of neo- 
arsphenamine are: 

(1) But a single ampule should be dissolved at a time. This drug must 
not be dissolved in bulk to be given to a series of patients. 

(2) Cold water only should be used. 

(3) The dilution should be not stronger than 0.1 gm. of the drug in 2 c. c. 
of freshly distilled water. 

(4) A very small needle should be used, and the time of injection of the 
dose should be not less than five minutes. 



ioo THE TREATMENT OF SYPHILIS 

CAUTION 

Operators are advised that they will be held responsible for untoward 
results following the use of arsphenamine and neo-arsphenamine in cases 
where there has been material deviation from the outline given above. 
Acknowledgment of receipt of this letter is directed. 

Respectfully, 

Rupert Blue, 
Surgeon General. 
Accidents 

Serious accidents practically never follow the proper intro- 
duction of a properly prepared arsphenamine solution into the 
circulation, i. e., when the physician's technic is perfect. There 
is no reason why perfection should not be attained, particularly 
when we consider that faulty technic endangers human life. 

A common accident is the penetration of the vein at a point 
opposite the proper place of entrance of the needle. As a result, 
the solution leaks into the surrounding tissue and the infiltration 
may develop a badly inflamed arm and a possible abscess with 
sloughing. Such an occurrence can be obviated by using a short 
beveled needle, and by first introducing sterile distilled water 
into the vein, until the operator is certain the flow is free and the 
needle properly in the vein. 

Acidity of the solution may bring about a phlebitis, with its 
attendant difficulties. 

Over-alkalinity of the solution may result in the formation of 
a thrombus, which will enter the circulation. Wounding of the 
vein may also cause a thrombus. 

Dr. Loyd Thompson of Hot Springs, Arkansas, reports (Syph- 
ilis, p. 238, 1916) the case of a physician who, finding that the 
blood did not flow freely through a needle inserted in an elbow 
vein, opened up the lumen of the needle with its stylet. A blood 
clot was undoubtedly pushed out of the needle into the vein, as 
the patient died before the solution was administered. 

Embolism may also follow the introduction of air into the vein 
on account of the failure of the operator to drive all the air out of 
the cylinders and tubing. 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 101 

Embolism may be caused by bits of cotton which enter the 
solution while it is being filtered. 

The Importance of Watching the Kidneys 

Patients have died during or soon after the administration of 
arsphenamine. We believe that in the majority of instances the 
fault is that of the operator, in that some important essential 
was overlooked. A physical examination of the patient, often 
neglected, might have revealed some contraindication. 

Urinary examinations are too seldom made by many physicians 
administering arsphenamine, who, forgetting this essential, can 
only trust to good fortune that the kidneys of their patients are 
in the proper condition to eliminate the arsenic. 

Dr. E. L. Keyes, Jr., of New York {Urology, p. 829, 1917) is 
of the opinion that acute congestion of the kidneys is the most 
common cause of death. He gives acute encephalitis as another 
casus morti. 

He advocates a careful examination of kidneys and urine, and 
advises that if the urine reveals albumin and casts and if it 
shows a deficient excretion of urea the physician inject only a 
third or a fourth of the usual dose of arsphenamine. 

Col. E. B. Vedder, U. S. Army (Syphilis and the Public Health, 
p. 287, 191 8) lays particular emphasis on the condition of the 
kidneys at the time of treatment. He notes that in fatalities 
occurring in patients in the active secondaries two or three days 
after the injection, they presented symptoms resembling uremia. 
He observes that in three and one half years four fatalities oc- 
curred in over 31,000 injections and that three of the four cases 
on autopsy revealed an intense acute nephritis. 

Wechselmann (The Pathogenesis of Saharsan Fatalities, St. 
Louis, 1 913) believes that some deaths following the use of sal- 
varsan are due to previous injuries by mercury to the kidneys, 
which are thus unable to eliminate the arsenic. 

Animal Experiments Reveal Interesting Facts 

Fatalities follow in an exceeding small percentage of cases. 
The percentage is, doubtless, between 1/50 and 1/100 of 1 per 



102 THE TREATMENT OF SYPHILIS 

cent, a number almost negligible. Such a factor must, however, 
be considered, and we are, therefore, interested in some of the 
animal experiments of D. E. Jackson and M. I. Smith of the 
Division of Pharmacology of the Hygienic Laboratory, United 
States Public Health Service. {Jour. Phar. and Exper. Therapy 
Vol. XII, No. 4, 1918.) They made an analysis of the effects of 
various arsphenamine preparations on the cardio-vascular ap- 
paratus for the purpose of ascertaining the cause of acute reac- 
tions, and examined various remedies in the search for an efficient 
method of treating acute collapse from the drug. 

Alkaline solutions were used. When a dose, averaging the 
amount usually used in the clinic at the Hygienic Laboratory, 
was injected slowly there was little or no immediate cardio- 
vascular change observed, but acceleration of the injection rate 
and an increase in the dose produced definite effects. The first 
of these was a slight but gradually progressive dilatation of the 
heart and a slow fall of blood pressure. 

A rapid injection, it should be noted, is likely to cause a rather 
marked, sudden fall of blood pressure. 

Large doses of arsphenamine caused a variety of vascular 
reactions of the internal organs, such as dilatation of the spleen, 
contraction of the kidney and dilatation of the intestinal vessels. 

Further experimentation demonstrated that if a dose of 
30 mgm. per kilo of a 2 per cent arsphenamine solution were in- 
jected in a dog rapidly, i. e., within three or four minutes, the 
pulmonary blood pressure might be increased 100 per cent or 
more and a marked fall in systemic blood pressure was likely 
to occur. 

The authors feel that under the unusual conditions under 
which the heart must work when enormous rises in pulmonary 
blood pressure are produced by large doses of the drug, the heart 
may be so strained that delirium cordis may well be expected. 

They are of the opinion that the alkalinity of the arsphenamine 
solution alone may be responsible for a considerable degree of 
rise in pulmonary blood pressure, but they also believe that the 
specific action of the arsenic compound is responsible for part 
and may be most of the increase in pulmonary arterial tension. 



REACTIONS FOLLOWING USE OF ARSPHENAMINE 103 

They emphasize the fact that rise in pulmonary pressure was 
observed only when large doses of the drug were injected. 

They further state that, while large doses of concentrated 
alkaline solutions rapidly injected always produced marked rises 
in pulmonary blood pressure, slow injections of dilute solutions 
brought about no visible rise in pulmonary pressure. 

Important Role Played by Disturbance of Pulmonary Circulation 

Jackson and Smith are, therefore, led to the belief that a 
disturbance of pulmonary circulation is one of the chief factors 
when patients complain of faintness, dyspnea and circulatory 
disturbances. 

Moderate doses of a good arsphenamine preparation slowly 
injected produced but little effect on the respiration, but as the 
action of a large dose developed the respiration became slower 
and shallower. 

Respiratory embarrassment is the result of depression of the 
respiratory center and of a greatly depressed circulation. Artifi- 
cial respiration proved of no avail. 

In experimental arsphenamine intoxication, Jackson and 
Smith found that respiratory failure was probably the immediate 
cause of death, as the heart usually beat a short time after 
breathing ceased. 

If a rapid injection of a toxic preparation was given frequently 
the heart and respiration stopped simultaneously. 

The experimenters, in their search for the trouble-making 
properties, carefully went into the effects produced by the inter- 
mediary and oxidation products which are formed in the process 
of manufacture of arsphenamine, but they were satisfied that 
none of these play a significant role in acute toxic action. 

Danysz (Ann. de VInst. Pasteur, Paris, No. 3, p. 114, 191 7) 
believes that arsphenamine in alkaline solutions may undergo 
precipitation in the blood stream, thus forming insoluble masses 
which tend to lodge in the smaller blood vessels, especially in the 
pulmonary vessels, thus giving rise to serious symptoms. He 
thinks that later these insoluble masses again undergo solution, 
due to the solvent action of the blood and tissue juices, which, 



104 THE TREATMENT OF SYPHILIS 

combining with the masses of arsphenamine, form soluble, 
organic compounds which are carried by the blood stream to the 
tissues of the body. 

Jackson and Smith endeavored by a series of experiments to 
corroborate this theory, but without success. They found the 
toxicity of arsphenamine was not effected, nor could they demon- 
strate with alkaline solutions that precipitation and embolism 
occurred. 

The Use of Tyramine in Cases of Collapse 

For the treatment of acute arsphenamine collapse Jackson and 
Smith suggest tyramine (parahydroxyphenylethylamine) which 
can be given intravenously in time of emergency or intramuscu- 
larly or subcutaneously. They say they have prolonged the 
lives of animals severely poisoned with arsphenamine by intro- 
ducing intravenously 10 mgm. of tyramine into animals weighing 
from 5 to 10 kilos. The drug stimulates the heart and produces a 
prolonged and sustained rise in systemic blood pressure. The 
effects of tyramine progressively decrease after the initial rise in 
pressure, which requires from one to five or more minutes for its 
full development. The investigators say the systemic pressure 
does not rise so high and the danger of acute dilatation of the 
heart is not so great as with the intravenous injection of epineph- 
rin, but the effects of tyramine are much more lasting. 

Hewlett (Arch. Int. Med., XXI, 411, 1918) has injected 
tyramine hypodermically in doses of 40 to 80 mgm. with an 
average of 60, and has been satisfied with it as a blood-pressure 
raising agent. It also seems to improve the circulation. 

The consensus of the best opinion is that few fatalities result 
from the toxicity of the arsphenamine itself but that the results 
usually come from imperfection in technic, physical inability of 
the patient to assimilate arsenic or metabolic changes in the 
system not as yet understood by physiologists. 



CHAPTER XI 

THE WASSERMANN REACTION AND THE EFFECTS OF TREATMENT 

THEREON 

The Provocative Wassermann Reaction 

After a luetic patient is believed to be free from the spirocheta 
pallida it is the practice of most syphilologists to give a pro 
vocative injection of salvarsan. Gennerich (Ber. Klin. Woch., 
1 910, No. 38) reported that negative Wassermann reactions 
often changed to positives after a salvarsan injection. Thus we 
are able to demonstrate the effectiveness of our treatment by a 
provocative injection. 

Our procedure is to inject 0.3 salvarsan intravenously and 
have a Wassermann done every day thereafter for six days, by 
which time the change of the reaction will be effected, if there is 
any cause to change. It is well, however, to have Wassermanns 
also done on the 8th, 10th, 12th and 14th days after the pro- 
vocative injection, as the reaction may be unduly delayed. 

If spirochetal are in the system their presence will probably 
be made known by this method. If a negative Wassermann re- 
mains negative after a provocative injection, and all other 
standards are fully met, we have a right to conclude that the 
patient is cured. (See pp. 152-153.) 

Drs. John H. Stokes and Paul A. O'Leary of the Mayo Clinic 
in an enlightening paper on this subject (Am. Jour. Syph., i, 629, 
191 7) presents these indications for the provocative injection: 

"1. A definite history of primary or secondary lesions or a 
suspicious genital sore of any description. (With a negative 
Wassermann.) 

"2. Syphilis in husband or wife or a history of a sore in either. 

"3. Treated cases to determine the fact of cure or need for 
further treatment. One-third of the cases thus tested by us, 
gave a positive provocative effect. 

"4. Obscure bone or joint lesions. 



106 THE TREATMENT OF SYPHILIS 

"5. Histories of miscarriages unless the anatomical cause is 
glaringly obvious. 

"6. Mothers of syphilitic children without clinical signs of the 
disease. 

"7. Cases with a history of a positive Wassermann elsewhere, 
negative on present examination. 

"8. Mental deviates and constitutionally inferior individuals 
with suspicious histories. 

"9. Certain signs elicited by special examinations, such as 
decreased bone conduction with normal hearing, chorioretinitis 
and retinitis pigmentosa, bilateral dacryocystitis in childhood/ ' 
etc. 

The Effect of Arsphenamine and Mercury upon the Wassermann 

Reaction 

A careful study of the literature upon this subject since sal- 
varsan first appeared shows the effect of the fallacious belief 
that one injection will completely kill all the treponemata and 
cure the patient. In the earlier days many cases relapsed 
within a year because mercurial treatment had not been used 
in conjunction with salvarsan or on account of too little treat- 
ment. 

Today, when we realize that the system must be flooded with 
anti-luetic agents, the number of cases relapsing has been re- 
duced to a minimum. 

In acute cases, treated before the Wassermann has become 
positive, we are usually able to keep it negative if vigorous treat- 
ment is employed. 

In acute cases in which the first examination reveals a positive 
reaction, regular salvarsan treatments and mercury injections 
generally change the positive to a negative in from four to eight 
weeks. 

When primary cases are treated, as is our custom, with eight 
injections of arsphenamine, at from five to seven day intervals, 
and with mercurial injections or inunctions for twelve weeks, 
the chances strongly favor a continuous negative reaction, unless 
something unforeseen occurs. 



THE WASSERMANN REACTION 107 

In cases of long standing, several courses may be necessary 
to change the reaction. One of our cases, a man sixty-four 
years old, with a history of luetic infection twenty-one years 
before presenting himself to us, took seven courses, with the usual 
amount of mercury, before a negative reaction was obtained. 
The subsequent results, however, justified this persistent effort. 

The consensus of opinion is that conjoint arsphenamine and 
mercury treatment, faithfully and intelligently administered, will 
usually produce a negative reaction in primary positive cases in 
two months or less, and that in long-standing cases consistent 
treatment will eventually bring about a permanent negative in a 
majority of cases except in those aortic or cord lesion cases, 
which are irresistible to treatment from a serological standpoint. 

The Definite Serological Effect of Arsphenamine 

Many years must necessarily elapse before we can say with 
absolute certainty that salvarsan and mercury have a real defi- 
nite and lasting action upon the Wassermann reaction. 

We know the action of mercury as a medicinal agent, for it 
has been utilized as an antiluetic for centuries. 

Since the Wassermann reaction became known the medical 
profession has had ample opportunity to study the effect of 
mercurial treatment in connection with that reaction. 

It is, however, too early to make affirmative statements re- 
garding salvarsan's permanent effacement of the positive Wasser- 
mann. 

Experience has taught us that mercury has not been the ef- 
fective spirocheticide that our medical forebears considered it. 
Relapses under mercury were not uncommon. Many an un- 
fortunate syphilitic was lulled into security by the disappearance 
of outward symptoms under mercury and its accompanying 
medication, only to awaken after a period of years to the hor- 
rible realization of tabes, paresis and other sequelae which are the 
results of an invasion of the treponemata. 

We indulge the hope that salvarsan produces a more per- 
manent effect on the system and that relapses will be less com- 



108 THE TREATMENT OF SYPHILIS 

mon following its proper use, but sufficient time has not elapsed 
to verify this hope sufficiently to make it an undisputed fact. 
However, as Col. Charles F. Craig, U. S. Army, well says, it has 
been demonstrated that in the treatment of lues mercury is of 
small value, when compared with salvarsan. 

He states (The Wassermann Test, 1918, p. 184) "for one case 
that becomes negative after treatment with mercury there are 
hundreds that become negative after treatment with salvarsan, 
and although the majority of both classes of cases relapse in 
time and again present a positive Wassermann reaction, the 
relapses are much less frequent among patients treated with 
salvarsan than with mercury." 

Positive Results from Salvarsan and Mercury 

The effect of salvarsan and mercury upon the Wassermann re- 
action is not, fortunately, a matter of conjecture. 

The work of Craig and of other careful observers has proved 
that we have something real to look forward to as a result of the 
combination of these two antiluetics. Craig (ibid.) continues : 

"The relative efficiency of salvarsan and mercury in causing a 
disappearance of the Wassermann reaction is well illustrated in 
patients who had previously been treated with mercury before 
receiving salvarsan. Of 90 patients who were treated with mer- 
cury by the mouth for nine months or more before the adminis- 
tration of salvarsan and who gave a positive Wassermann re- 
action, 68, or 70.5 per cent became negative within eight weeks 
after the administration of the drug. The intensity of the re- 
action at the time of receiving salvarsan and the length of time 
the patients had been taking mercury is shown in this table: 



THE WASSERMANN REACTION 



109 



The Wassermann Test in Patients Who Had Taken Mercury for 
Various Periods of Time (After Craig) 



Method of 


Time of 
Treatment 


Number 
of Cases 


Character of the Reaction 


Treatment 


++ 


+ 


+ - 


Mercury by mouth 

tt u a 
a tt tt 


9 months 

1 year 

2 years 

3 years 


17 
26 

17 
8 


8 

16 
7 
3 


7 
8 

9 

4 


2 
2 

1 
1 


Totals 




68 


34 


28 


6 



"The table shows that 26 of these patients had taken mercury 
by mouth for a period of one year and that 16 of them still gave 
a four plus reaction; that 17 had received the same treatment for 
two years, of whom 7 still gave a two plus reaction; and that 8 
had received treatment for three years, of whom 3 still gave a two 
plus reaction. Of the 68 cases not one had become negative as 
the result of mercury administered by the mouth, but after the 
administration of salvarsan every one became negative within 8 
weeks. This is certainly very decisive proof of the greater specific 
action of salvarsan and could only be ascertained by the effect 
of the drugs in question upon the Wassermann reaction. 

"Objection may be raised to the results recorded above by 
calling attention to the fact that the administration of mercury 
by mouth is now well recognized to be the poorest of all ways of 
giving this drug, although it is not so long ago that three years ' 
treatment by mouth with mercury was considered by the best 
authorities upon the disease as adequate for the cure of syphilis. 
In answer to this objection another table is given, covering 18 
patients treated with hypodermic injections of mercury, a plan 
of treatment generally acknowledged to be the most efficient of 
the many ways of administering the drug. For purposes of com- 
parison the effect upon the Wassermann of treatment with sal- 
varsan is also included. 



no 



THE TREATMENT OF SYPHILIS 



The Comparative Results of Treatment with Mercury and Salvarsan 
upon the wassermann reaction (after craig) 





Mercurial Treatment 


Salvarsan Treatment 


Number of 
















— - 


Cases 


Injections of 
Gray Oil 


Character of 
Reaction 


Dose 0.6 gm. 


Character of 
Reaction 


2 


7 


++ 


Intramuscular 





i 


8 


+ 


tt tt 


— 


i 


9 


++ 


tt It 


— 


i 


ii 


++ 


tt tt 


— 


3 


15 


++ 


Intravenous 


— 


i 


15 


+ 


Intramuscular 


— 


4 


18 


++ 


a ti 


— 


2 


19 


++ 


Intravenous 


— 


I 


20 


++ 


u ti 


— 


I 


25 


+ 


Intramuscular 


— 


I 


30 


+ 


tt it 


— 



"From a consideration of this table it is evident that cases 
having had as many as 18 to 20 injections of gray oil still gave a 
two plus Wassermann reaction and that cases having as high as 
25 and 30 injections still gave a three plus reaction. After the 
administration of salvarsan all became negative within 8 weeks, 
and in 12 of the cases only one intramuscular injection of 0.6 
gm. of salvarsan was administered. While there is reason to 
believe that previous treatment with mercury may have had 
something to do with the good effects produced by salvarsan 
upon the reaction, it must be admitted that the results obtained 
in these cases demonstrate beyond all question the superior 
specific value of salvarsan upon treponema pallidum. 

"Patients who have been previously well treated with mercury 
show a higher percentage of negative results after treatment with 
salvarsan than those who have received no mercurial treatment. 
Thus of 75 patients who had received mercurial treatment before 
receiving salvarsan, 84 per cent became negative, while of no 
patients who had received no treatment before the administra- 
tion of salvarsan, only 74.5 per cent became negative. 

"In order to illustrate the persistence of the positive Wasser- 



THE WASSERMANN REACTION 



in 



mann reaction after treatment with mercurials, another table has 
been prepared giving the method of treatment, the length of time 
the patient was under treatment, the number of cases observed, 
and the intensity of the reaction. 

Illustrating the Persistence of the Wassermann Reaction after 
Treatment with Mercury (after Craig) 



Method of 


Length of 
Treatment 


Number of 
Cases 


Intensity of the Reaction 


Treatment 


++ 


+ 


+- 


By mouth 


i month 


2 




2 








2 months 


3 


1 


2 








3 " 


4 


2 


2 








5 " 


6 


3 


3 








6 " 


10 


7 




2 






7 " 


4 


3 










8 " 


5 


4 










9 " 


10 


7 




2 






IO " 


3 


2 










ii " 


3 


3 










i year 


24 


13 


6 


5 






14 months 


2 


2 










IS " 


2 


1 


1 








16 " 


4 


3 




1 






i7 " 


1 


1 










18 " 


7 


1 


4 


2 






19 " 


4 


3 


1 








20 " 


2 


1 


1 








2 years 


IS 


8 


S 


2 






2.5 " 


3 




2 


1 






3 " 


S 


1 


2 


2 






4 " 


1 


1 






By mouth* 


7 " 


1 




1 




By mouth* 


10 " 


1 


1 






By mouth* 


12 " 


1 




1 




Inunctions 


2 months 


2 


2 






u 


5 " 


1 




1 




u 


6 " 


2 


2 






<< 


1 year 


1 


1 







* Interrupted treatment during this time. ++ indicates complete in- 
hibition of hemolysis. 



H2 THE TREATMENT OF SYPHILIS 

Mercury not a Staple Curative Agent 

"The table illustrates very well the effect of treatment with 
mercury upon the Wassermann reaction, as it occurs in the usual 
routine of serological work in a Wassermann laboratory. It 
shows that continued treatment with the drug for long periods 
of time has but little effect upon the reaction in the majority of 
instances and that interrupted treatment continued for many 
years does not produce a negative reaction in many cases. 

"It should not be thought, however, from the data given here, 
that the Wassermann reaction never becomes negative after 
treatment with mercury, for in a considerable proportion of 
cases it does, and the writer has observed many cases in which a 
negative Wassermann reaction was obtained after from one to 
two years ' proper treatment with this drug, but it has been his 
experience that most cases becoming negative after mercurial 
treatment relapse in the course of months or a year or two. While 
he would not go so far as to state that the Wassermann test never 
becomes permanently negative after treatment with mercury, 
it has been his experience that it is only in very rare instances that 
a permanently negative result is obtained from treatment with this 
drug alone, no matter how it is administered or in what dosage. 

"In fact, it has been proved in rabbits experimentally infected 
with syphilis, that before the animals can be rendered sterile 
as regards treponema pallidum so much mercury has to be ad- 
ministered as to cause either the death of the animal or very 
serious pathological lesions due to the drug. In the writer's 
rather large experience he has never personally followed a case 
treated with mercury alone, in which the Wassermann test was 
positive before treatment, that became permanently negative, 
although many cases have lost the positive reaction for a while 
but have invariably become positive again upon the cessation 
of treatment. However, that mercury does cure syphilis in some 
instances, is proved by the fact that individuals are encountered 
who undoubtedly had the disease but who have been without 
symptoms for many years and who give a negative Wassermann 
reaction whenever tested. 



THE WASSERMANN REACTION 113 

"If the patient's blood serum be carefully titrated after the 
administration of either salvarsan or mercury, it will be found 
that in almost every instance the Wassermann reaction is in- 
fluenced to some extent, although it may never become negative. 
Thus, many cases showing a two plus reaction, or absolute in- 
hibition of hemolysis, with quantities of blood serum as small as 
0.02 c. c. will become negative for this amount of serum, although 
giving a positive reaction with the usual quantity of serum used 
in the routine tests; i. e., 0.1 c. c. By titrating the inhibitory 
strength of each patient's serum it will be found that, although 
the Wassermann test may apparently be uninfluenced when the 
diagnostic amount of serum is used, that is, 0.1 c. c, some diminu- 
tion in the strength of the reaction will be observed in amounts 
less than 0.1 c. c. In using the Wassermann test as a control of 
treatment the titration of the patient's serum is of great im- 
portance, as will be noted. 

"Not only will treatment with salvarsan or mercury markedly 
influence the strength of the reaction but if treatment is com- 
menced early in the primary stage of the disease it will sometimes 
prevent the development of a positive reaction, although clinical 
symptoms may occur." 



CHAPTER XH 

THE TREATMENT OF SYPHILIS OF THE CENTRAL NERVOUS SYSTEM 

It is unnecessary in a book, enabling the general practitioner 
to formulate a technic for the ordinary uses of salvarsan and 
neosalvarsan, to discuss in elaborate detail the treatment of 
syphilis of the central nervous system. For purposes of informa- 
tion, however, the method of utilizing salvarsan in the direct 
treatment of interstitial and parenchymatous lues are herein 
briefly set forth. 

Swift-Ellis Method 

This method was brought to the attention of the medical 
profession by Drs. Homer F. Swift and Arthur M. W. Ellis, of 
New York, in 191 2 (N. Y. Med. Jour., July 13, 191 2) and, with 
some modifications, is still in use. 

The original technic was to withdraw the blood into large tubes 
by means of a MacRae venous puncture needle, after intravenous 
injections of salvarsan or neosalvarsan, to separate the serum and, 
on the following day to dilute it to 40 per cent with normal saline 
and to heat it at 5 6° C. for thirty minutes. By lumbar puncture, 
15 c. c. of spinal fluid was withdrawn, and then 30 c. c. of the 
diluted serum was warmed to body temperature and was slowly 
injected into the subarachnoid space. The foot of the bed was 
raised for one-half hour after treatment. Drs. Swift and Ellis 
found that there might be a slight rise in temperature after the 
injection, and that in tabetics there were often lightning pains in 
the legs. The reaction usually passed off by the following day 
and the patients were able to be up and around the hospital. 

In concluding their original article, they observed that the 
best results could probably be obtained from the intravenous 
treatment with salvarsan or neosalvarsan, combined with in- 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 115 

traspinous injections of the patient's own serum, possibly with 
the addition of small amounts of neosalvarsan. 

Technic of Subarachnoid Injections 

Drs. Swift and Ellis read a paper before the Association of 
American Physicians, May 7, 19 13, in which they set forth the 
following technic of subarachnoid injections: 

"One hour after the intravenous injection of salvarsan 40 c. c. 
of blood is withdrawn directly into bottle-shaped centrifuge 
tubes, and allowed to coagulate, after which it is centrifugalized. 
The following day 12 c. c. of serum is pipetted off and diluted 
with 18 c. c. of normal saline. This 40 per cent serum 1 is then 
heated at 5 6° C. for one-half hour. After lumbar puncture the 
cerebrospinal fluid is withdrawn until the pressure is reduced to 
30 mm. cerebrospinal fluid pressure. The barrel of a 20 c. c. 
Luer syringe (which has a capacity of about 30 c. c.) is connected 
to the needle by means of a rubber tube about 40 cm. long. The 
tubing is then allowed to nil with cerebrospinal fluid so that no 
air will be injected. 

"The serum is then poured into the syringe and allowed to 
flow slowly into the subarachnoid space by means of gravity. 
At times it is necessary to insert the plunger of the syringe to 
inject the last 5 c. c. of fluid. It is important that the larger part 
of the serum should be injected by gravity and if the rubber tub- 
ing is not more than 40 cm. long the pressure cannot be higher 
than 400 mm. Usually the serum flows in easily under even a 
lower pressure. By the gravity method the danger of suddenly 
increasing the intraspinous pressure to the danger point, such 
as might occur with rapid injection with a syringe, is avoided. 
Frequently there is a certain amount of pain in the legs, com- 
mencing a few hours after the injection. The pain is more often 
noticed in tabetics than in patients with cerebrospinal syphilis. 
It can usually be controlled by means of phenacetin and codein. 
Occasionally morphin is required." 

x In patients who do not have reactions following the injection of 40 
per cent serum, the strength is at times increased to 50 or 60 per cent, or 
even stronger. 



n6 THE TREATMENT OF SYPHILIS 

Continued observation demonstrated to their satisfaction 
that this method had a curative action on the syphilitic process 
and that, where especially intensive treatment was required, as in 
rapidly advancing tabes or paresis, or where the disease had 
resisted other forms of treatment, it was especially indicated. 

Observations on Types of Response 

Dr. Swift's last paper read before the College of Physicians, 
Philadelphia, February 7, 191 7, is on his Observations on Types 
of Response in the Treatment of Syphilis of the Central Nervous 
System (Amer. Jour. Syph., Vol. 1, No. 3, July, 19 17). He 
classifies the various types under the following main headings: 

1. Vascular. — The essential lesion is an endarteritis, and the 
nervous lesion is due to disturbed circulation. 

2. Exudative. — The most marked lesion is cellular thickening 
of the supporting membranes or perivascular spaces, with gumma 
formation and subsequent mechanical injury to cortex, tracts, 
and intradural portions of nerves. 

3. Parenchymatous. — The striking picture is tract or cortical 
degeneration, but in which the essential lesion is probably a 
chronic meningitis and perivasculitis. At least this appears to 
be true of the various tabetic manifestations. In paresis a true 
inflammation of the cortex seems to exist. This peculiarity in 
the paretic process probably explains the intractability of this 
condition to treatment. 

The various factors considered in classifying the cases have 
been found by Dr. Swift to be: time since infection; the clinical 
picture; the laboratory findings; and the response to treatment. 
He recognizes these groups: 

1. Early Meningitis. 

(a) Cases which respond readily to the general administration 
of salvarsan and mercury. 

(b) Cases which respond more slowly to salvarsan intra- 
venously, and tend to relapse when salvarsan is discontinued, or 
mercury is substituted. 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 117 

(c) Cases which do not clear up under most intensive general 
treatment, but which respond satisfactorily to intraspinal treat- 
ment. 

2. Later Forms of Central Nervous Syphilis of the Exudative 
Type. 

The abnormal elements in the cerebrospinal fluid usually 
disappear rapidly under general administration of iodides, mer- 
cury and salvarsan. 

3. Tabes Dorsalis. 

(a) Cases which show a rapid response to general treatment. 

(b) Cases which show no improvement or very slow improve- 
ment under general treatment. 

(c) Cases which show a satisfactory response to intraspinal 
treatment alone. 

(d) Cases which have responded slowly to general treatment, 
but which respond more rapidly when intraspinal injections of 
"autosalvarsanized serum" are given. 

(e) Cases which relapse when treatment is discontinued. 

(f) Cases which continue to improve when treatment is dis- 
continued. 

4. Paralytica Dementia. 

(a) Cases with marked improvement in both clinical signs and 
the condition of the cerebrospinal fluid. 

(b) Cases with marked clinical improvement but no change 
in the cerebrospinal fluid. 

(c) Cases with progressive downward clinical course and 
stationary condition of the cerebrospinal fluid. 

5. Patients Clinically not Paralytica Dementia in whom the 
Cerebro-spinal Fluid shows a Paretic Type of Gold Curve. 

(a) Cases which respond rapidly to combined intravenous and 
intraspinal treatment. 

(b) Cases which respond more slowly and show a decided 
tendency for the abnormal elements to recur when treatment is 
discontinued. 



n8 THE TREATMENT OF SYPHILIS 

Summarized Conclusions 

The conclusions reached, following a very comprehensive 
study of the conditions, are: 

" Before undertaking the treatment of a patient with any form 
of cerebrospinal syphilis, it is important to determine what 
symptoms are due to inflammation or exudation and what are 
due to degeneration of tracts or cortex. It is also advisable to 
determine the intensity of the irritative condition as indicated by 
the cerebrospinal fluid. In general the lesions due to inflamma- 
tion or exudation are much improved or eliminated by the 
general treatment of the. patient. Those due to degeneration 
are little, if any, affected. 

" Treatment should be directed not only towards the elimina- 
tion of symptoms, but towards the elimination of the underlying 
process, namely, syphilis. In most patients with early meningitis 
and in those with what was formerly termed tertiary syphilis 
of the central nervous system, the symptoms due to exudation 
respond in a satisfactory manner to the general administration of 
salvarsan, mercury, and potassium iodid. 

" Occasionally, a case is met in which intraspinal treatment 
seems to be necessary in order to eradicate completely the cen- 
tral nervous lesions. Likewise in tabes dorsalis, many cases 
respond satisfactorily to the general administration of salvarsan 
and mercury. On the other hand, in a considerable number of 
tabetics, the addition of intraspinal injections of serum to in- 
travenous treatment with salvarsan seems to hasten the elimina- 
tion of abnormal elements in the cerebrospinal fluid and leads 
to a permanent arrest of the degeneration. 

"It is advisable to continue the treatment of patients suffering 
from cerebrospinal syphilis or tabes dorsalis until the cerebro- 
spinal fluid is normal and remains so. A possible exception may 
be made in reference to excess globulin, for an increased globulin 
is not infrequently found years after all other abnormal elements 
have disappeared from the fluid. 

"In paralytica dementia, while much benefit may be expected 
in increasing the number and length of remissions, the ultimate 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 119 

hope for recovery is slight. When a paretic type of gold curve is 
found in the fluid of patients in whom the clinical diagnosis of 
paresis is not justified, the most intensive form of treatment 
should be instituted from the beginning. It is probable that the 
finding of this paretic type of gold curve often helps us to make a 
diagnosis of paresis before clinical symptoms of the disease are 
present. This early diagnosis with consequent early treatment 
may be of extreme importance in preventing the development of 
the outspoken condition. 

"Finally, treatment must be individualized, given in courses, 
and the condition of the fluid determined at the end of each 
course and at the beginning of the subsequent course. In this 
way, the indication for kind of treatment, as well as the manner 
of response, is much more certainly determined than if we de- 
pend on clinical symptoms and objective findings alone." 

Dr. Ogilvie's Modification 

Dr. Hanson S. Ogilvie of New York, believes it necessary to 
eliminate the uncertain salvarsan content of the Swift-Ellis 
serum by preparing in vitro a serum of definitely known thera- 
peutic value. His technic is as follows (Amer. Jour. Syph., 
Vol. I, No. 3, July, 191 7): 

"Ten cubic centimeters of clear human serum are obtained 
either by centrifuging a tube of freshly drawn blood at approxi- 
mately 3000 revolutions for from ten to fifteen minutes, or per- 
mitting a clot to form by letting it stand overnight. (Originally 
15 c. c. was recommended, but it has since been found that the 
smaller amount is sufficient, and productive of equally as good 
results.) It is not essential that an autogenous serum be em- 
ployed. 

"Sera taken indiscriminately from patients can be used, and 
where a large number of patients are to be treated the sera can 
be pooled and divided into amounts of 10 c. c. each. Care should 
be taken to free the serum absolutely from fibrin and cellular 
elements, and to this end it is sometimes necessary to centrifuge a 
second time. Under no circumstances should a serum be used 
that contains hemolized red blood cells. The test tube containing 



120 THE TREATMENT OF SYPHILIS 

the serum is then placed in a water bath at body temperature 
until the salvarsan is ready to be added. 

11 In preparing the salvarsan solution the greatest care must be 
exercised in alkalinizing it. The sodium hydroxid solution must 
be fresh (preferably not more than four or five days old), and 
only a sufficient amount added to very faintly alkalinize the sal- 
varsan solution. The salvarsan solution will be more readily 
and accurately alkalinized if the sodium hydroxid is added while 
the former is about body temperature. 

"A very hot salvarsan solution requires more sodium hydroxid 
to faintly alkalinize it, but when it is cooled down the degree of 
alkalinity is apparently markedly increased, and a serum charged 
with such a solution invariably produces a reaction (usually root 
pain) when given intraspinal^. The salvarsan solution should 
be prepared so that each cubic centimeter contains one milligram 
of the drug. While at first thought of minor importance, this 
part of the technic should be carefully considered. 

"Unless one is familiar with laboratory work to some extent 
he is liable to miscalculate his dilution strengths and give more 
of the drug than is intended. With a i c. c. pipette, graduated 
into tenths or twentieths, the exact amount of salvarsan desired 
for the case under treatment is added to the ten cubic centimeters 
of serum, care being taken that the two solutions are at the same 
temperature (preferably 37.5 C). The serum should then be 
gently agitated to insure thorough mixing. It is now placed in a 
water bath thermostat at 37.5 C. for forty-five minutes. From 
this it is placed in a thermostat at 56.0 C. for thirty minutes, 
after which it is removed from the water bath and as soon as the 
temperature is reduced to approximately that of the body, it is 
ready to be given to the patient." 

Suggestions in Intraspinal Treatment 

No changes have been made in this technic since 191 7. Dr. 
Ogilvie insists that the serum should be given not later than 
three hours after it is removed from the last thermostat, and that 
the treatment is better borne if it be given within an hour of its 
preparation. 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 121 

He also states that salvarsan and not neosalvarsan should be 
employed for intraspinal injection. 

In paresis Dr. Ogilvie employs a relatively stronger serum than 
in other types of neurologic syphilis, but he states that the max- 
imum amount of salvarsan that can be given with safety is one- 
half of a milligram, and that treatments with this strength should 
rarely be repeated of tener than every two weeks. 

He decries making a lumbar puncture with the patient sitting 
up, and he warns that after the treatment the patient should be 
kept on his back without pillows for from five to six hours and 
in a recumbent position for from thirty-six to forty-eight hours. 

He lays particular emphasis on the fact that while intraspinal 
treatment is of the greatest value in certain types, such as the 
interstitial (formerly referred to as the cerebrospinal), it can 
accomplish little more than the intravenous in others, such as 
the parenchymatous; and, furthermore, that not every case of 
interstitial syphilis of the central nervous system, where the cord 
or the cerebrum is involved, requires intraspinal treatment. A 
relatively small percentage of cases apparently respond quite as 
well to intravenous treatment with mercury intramuscularly. 

Dr. Ogilvie is further of the opinion that physicians generally 
have the impression that every one of these cases should be 
treated intraspinally, but he says that a careful study of the 
cerebrospinal fluid findings and the clinical picture presented 
should decide which course is the proper one to pursue. 

A Persistent Positive Means a Spirochetal Focus 

The physician has to bear in mind that a persistent positive 
Wassermann always indicates a spirochetal focus in the body. 
These may be in a quasi-harmless symbiosis in an unimportant 
tissue of the body and, consequently, it is unnecessary to subject 
the patient to continuous courses of treatment. On the other 
hand, however, the offending focus may be in the nervous or the 
vascular systems and, therefore, a very thorough examination is 
demanded. The lumbar puncture and the cytologic examination 
of the cerebrospinal fluid, and use of the globulin test and the 
colloidal gold test and every other diagnostic test are absolutely 



122 THE TREATMENT OF SYPHILIS 

demanded. Syphilologists agree that even in the absence of 
signs pointing directly to invasion of the nervous system in the 
face of a Wassermann which continues persistently positive, the 
physician is justified in doing a lumbar puncture. 

Importance of Intraspinal Treatment 

Dr. John A. Fordyce of Columbia University, the leading 
authority on syphilis in the United States, in a paper entitled 
"Intra-spinal Therapy in Neurosyphilis" (Am. Jour. Syphl., 
Vol. Ill, No. 2, July, 191 9) says that until conclusion by clini- 
cal study, serology and autopsy findings leads to the belief that 
foci are established in the various tissues, it may require years to 
modify or destroy functional capacity. He believes that a com- 
plete cure is the exception rather than the rule unless treatment 
is begun in the early months of the infection. An aortitis or 
aortic insufficiency is not the result of a sudden invasion by 
spirochetes many years after the primary sore, but the effect 
of a slow tissue reaction due to the implantation of the organisms 
in the florid stage of the disease. In the central nervous system 
the spirochetal attacks may cause marked subjective or objective 
symptoms and signs like headache, delirium or paralysis. On 
the other hand, an individual so infected may remain free from 
all symptoms for years until some important center or tract is 
compromised. 

Dr. Fordyce believes that the spirochete may be deposited in 
the cerebral cortex during the period of generalization of the 
organisms, and remain hidden away in the deeper parts of the 
brain and, only in after years, will they produce a disturbance of 
function. In certain cases they may temporarily stimulate the 
intellectual powers and lead to achievements of more than 
normal brilliancy. 

The progress of the infection in the central nervous system 
may be modified or delayed by therapeutic agents, but it is 
seldom cured. The modified or delayed infection is latent for a 
time and then relapses. This condition may continue for years 
before it finally terminates in irreparable damage. 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 123 

Necessity of Locating the Focus of Infection 

Dr. Fordyce emphasizes the necessity of locating the focus of 
infection and his statistics show that a larger percentage of 
deaths are due to cardiovascular disease of syphilitic origin than 
to any other phase of the disease. Therefore, when a persistent 
positive serum reaction is present, he advises a careful exami- 
nation of the heart and aorta. 

A positive Wassermann reaction which remains uninfluenced by 
intensive treatment for years, or which returns after a discon- 
tinuance of treatment, is often caused by neurosyphilis without 
any or with very few objective signs. The blood reaction may 
become negative after treatment but it will be re-infected by 
the spinal fluid. Dr. Fordyce lays especial emphasis on this fact. 

During the past five years he has had a very large experience 
with intraspinal treatment, and he finds that a serum properly 
prepared and diluted with from 30 to 40 c. c. of spinal fluid be- 
fore introduction into the spinal canal may be employed without 
danger in a vast majority of patients in whom indications are 
present for its use. 

The Fordyce Technic 

"The patient is given an intravenous injection of salvarsan and 
approximately one-half hour later 50 c. c. of blood are withdrawn 
from an arm vein. This is permitted to clot over night in the re- 
frigerator. The next morning it is centrifugalized and the serum 
pipetted into a sterile tube. After a second centrifugalization 
to insure removal of all red blood cells the clear serum is pipetted 
into another tube. To this is added the desired amount of sal- 
varsan, namely: from x / IO to %, I / 3 or in certain cases of paresis 
% mg. This mixture is then inactivated at 55 to 5 7 C. for yi 
hour. 

"To arrive at the proper dosage for intraspinal therapy we 
make a dilution of salvarsan of which 30 c. c. represents 0.1 gram 
of the drug; 10 c. c. is then further diluted with 0.5 per cent 
saline solution to 35 c. c. of which 1 c. c. equals 1 mg. of salvarsan. 
In the administration of the medicated serum a lumbar puncture 



124 THE TREATMENT OF SYPHILIS 

is made and about 10 to 20 c. c. of fluid withdrawn. A small 
gravity tube with a capacity of about 40 c. c. is then attached 
to the needle and the fluid allowed to flow in until it holds about 
30 c. c. To this is slowly added the serum and the mixture is 
permitted to flow back into the canal." 

Types which call for Intraspinal Treatment 

Dr. Fordyce makes his position clear regarding the indications 
for intraspinal therapy in that he believes the method in ques- 
tion is of value "in certain types of neurosyphilis which fail to 
respond to treatment by other channels and in which the spinal 
fluid reveals an active syphilitic lesion. If a patient after in- 
tensive treatment with arsphenamine, mercury and potassium 
iodid shows little or no improvement in his symptoms, blood or 
fluid reactions, some other method of therapeutic attack would 
be clearly indicated. " 

He finds that intraspinal treatment has been followed by per- 
sistent negative phases and clinical improvement or cure and, he 
is therefore, much more convinced of its value. Since adding 
salvarsanized serum to 30 or 40 c. c. of withdrawn fluid and per- 
mitting the mixture to slowly return by gravity his results have 
been more rapid and striking. 

Dr. Fordyce has a list of seventy-five cases of various neuro- 
syphilitic types in which the findings are negative and many 
of them have been persistently so for periods of from one to three 
years. He observes that activation of latent foci or lesions in the 
central nervous system may follow the administration of mercury 
or salvarsan and cause an acute encephalitis and death. These 
so-called Herxheimer reactions as a rule subside and are followed 
frequently by clinical improvement. It is not always possible 
to foresee them but they can usually be prevented by a careful 
preliminary use of mercury and salvarsan in moderate doses 
before the use of salvarsanized serum intraspinally. 

Intraspinal Treatment in Preserving Vision 

Emphasizing the necessity of systematic eye examinations in 
all cases of lues, Dr. Fordyce expresses the opinion that every 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 125 

case of optic atrophy, whether primary or part of a tabetic or 
paretic syndrome, demands an examination of the spinal fluid 

at the earliest possible moment. In case the spinal fluid shows 
primary or associated meningitis, with other positive phases of 
syphilis, a method of treatment should be begun which offers 
hope of arresting the destructive process. His experience is that 
but little can be expected from mercury, potassium iodid or sal- 
varsan intravenously, and he believes that intraspinal treatment 
is indicated in optic atrophy where the fluid shows a meningitis 
with the positive phases of syphilis. 

Persistent intraspinal treatment when indicated by the fluid 
findings can arrest the progress of many cases and preserve the 
remaining vision. Salvarsanized serum directly introduced into 
the lumbar subarachnoid space diffuses itself more slowly and 
accomplishes less than when diluted outside the body with a large 
quantity of fluid. 

Dr. Fordyce feels that too little time has elapsed since begin- 
ning the examination of the spinal fluid in secondary syphilis to 
enable him to speak with certainty as to the type of early neuro- 
syphilis which may develop paresis. He has, however, spinal 
fluid tests which indicate the probable site of the syphilitic in- 
fection of the central nervous system and a large number showing 
to what degree these reactions resist therapeutic attacks which 
influence the more superficial types of neurosyphilis. He regards 
as of favorable prognostic import a spinal fluid which shows a 
positive Wassermann reaction in the lower dilutions with a 
luetic gold sol curve, that is so far as regards the positive develop- 
ment of paresis. A persistent reaction in the high dilutions, 
however, with a paretic curve is of graver significance. When 
little or no impression can be made on the Wassermann in the 
spinal fluid by persistent intraspinal treatment, the probable 
development of paresis must always be kept in mind. 

Encouraging Results in Pre-paresis 

He observes that the results obtained by the intraspinal treat- 
ment in pre-paresis when sufficiently prolonged at times are so 
encouraging that he feels justified in carrying it out to the limit 



126 THE TREATMENT OF SYPHILIS 

of the patient's endurance. He believes that with the careful 
technic now employed and with the proper preparatory treatment 
danger to the patient's life or possible damage to the cord or 
brain has been entirely eliminated. He remarks in this connec- 
tion that such treatment by the inexperienced without labora- 
tory facilities and proper serological control will certainly fail. 

Summary of Dr. Fordyce's Conclusions 

"Results following the treatment of syphilis are largely de- 
pendent on the age of the infection. For this reason the impor- 
tance of early diagnosis and energetic treatment have been em- 
phasized. 

"In early syphilis the spirochetes are numerous, widely dis- 
seminated and cause little or no tissue destruction, organisms 
accessible to the specific drugs are destroyed and in favorable 
cases cures are obtained. In a large percentage of cases, however, 
the treatment is not carried out in an intensive fashion and as a 
result the organisms persist in the viscera, cardio-vascular or 
nervous system and slowly cause tissue reactions and final de- 
generation. 

"A serological cure in cases of syphilis in the late secondary 
stage and following this is difficult to obtain and requires ex- 
pert knowledge in the use of our therapeutic agents. 

"When the central nervous system is invaded the problem is 
complicated by the highly organized nature of the tissues, the 
results of secondary degenerations and the inaccessibility of the 
spirochete in certain types of neurosyphilis. In the majority of 
cases a strain of spirochete invades the cerebrospinal axis before 
or during the treatment by drugs by the usual channels and fails 
to respond to continuous administration of antisphilitic agents 
given in this way. The progress of the infection may be delayed 
by drugs assisted by the defensive forces of the body. It is 
seldom cured. Clinical symptoms are modified or disappear for a 
time but usually return unless the serology of the spinal fluid and 
blood becomes negative for a definite period. 

"The control of the pathological changes in the brain and cord 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 127 

is only possible by repeated examinations of the spinal fluid. We 
have no definite data as to the number of cases of neurosyphilis 
cured by the older methods of treatment. Frequent relapses and 
eventual termination in degenerations of the majority of cases 
so treated lead to the belief that few were cured. The need, 
therefore, is for a more direct method of attacking spirochete in 
the central nervous system. 

Intensive Treatment Indicated 

"The intensive use of salvarsan intravenously combined with 
mercury and potassium iodid cures a definite number of cases. 
All methods of treatment fail in certain types of neurosyphilis 
because of the inability to reach the organisms in inaccessible 
localities and because of secondary degenerations of tissue which 
cannot be restored. Intra-spinal treatment is successful in cer- 
tain types which fail to respond to other methods or which be- 
come stationary after a definite clinical and serological improve- 
ment. 

"Success or failure in the use of intraspinal therapy depends 
on the technic employed and the persistence of the physician in 
carrying it out. Above all it depends on the cyto-biological in- 
dications which are present in the spinal fluid for initiating or 
persisting in this mode of therapy. 

"The cytology is usually the first phase to be influenced in 
persistent infections. In some cases treatment must be continued 
for from one to two years before a definite impression is made on 
the globulin content or the Wassermann reaction. Modification 
in the intensity of the globulin reaction is usually followed by a 
weakening in the strength of the Wassermann and by a change in 
the gold sol reaction. Rapid changes in the Wassermann reaction 
where strongly positive in the high dilutions, in my experience, 
do not occur except in cases of early syphilitic meningitis. In 
old cases of neurosyphilis a gradual diminution in the intensity 
of the Wassermann reaction is of good prognostic import and, 
when it finally becomes negative, cases I have examined after 
one, two and three years have shown no return of any of the 
previous phases." 



128 THE TREATMENT OF SYPHILIS 

Intravenous rather than Intraspinal Medication 

Another school favors the treatment of syphilis of the nervous 
system by intensive intravenous rather than intraspinal medica- 
tion. Dr. Bernard Sachs of Mt. Sinai Hospital, New York, is 
the leader of this school. He believes that by the intravenous 
method no lives are lost, no unnecessary paralyses result from 
treatment and far less harm will be done than if the intra- 
spinal method were generally adopted. He points out (Arch. 
Neur. and Psych., Vol. i, pp. 277-284, March, 1919) that the 
early and persistent use of arsphenamine intravenously ad- 
ministered makes the entire course of the disease far less pro- 
gressive than formerly. He thinks it no exaggeration to state 
that in innumerable cases he has been able to check the progress 
of the disease. He says " there is a vast difference between the 
acute infectious disorders and the more chronic syphilitic disease 
dependent on the difference in the manner of invasion in the 
toxic products formed and in the final habitat of the respective 
micro-organisms. 

"In general paresis and in tabes the chief lesions are within the 
substance of the brain or of the cord far removed from actual 
contact with the cerebrospinal fluid. It is for that reason almost 
impossible to bring the spirocheticidal remedy into immediate 
contact with the foci of disease unless these remedies can be in- 
troduced through the blood streams. It is only in the earliest 
stages of tabes dorsalis that the disease, as we have long since 
known, involves the meninges and the spinal ganglia; later on it 
sets up marked degenerative changes in the spinal tissue, and 
these secondary changes are entirely beyond the reach of the 
cerebrospinal fluid and its contents. In the remaining meningo- 
encephalitic and meningo-myelitic processes of specific origin, 
more or less exudative in character, we would suppose that spiro- 
cheticidal substances introduced in the cerebrospinal fluid might 
have an active therapeutic effect if such substances could course 
freely in the cerebrospinal fluid and if it could be shown that they 
were retained in this fluid for any satisfactory period of time. 

"Four years ago, with the assistance of Professor Benedict, 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 129 

we succeeded in showing that salvarsan introduced in the usual 
quantities into the blood current appeared in the cerebrospinal 
fluid in appreciable quantities. In this way we refuted the doc- 
trine of the impermeability of the choroid plexus and that sal- 
varsan introduced intravenously could not be expected to exert 
any influence over the cerebral and spinal tissues. The question, 
therefore, narrowed itself practically to this: Whether or not as 
much spirocheticidal substances — for example, arsphenamine — 
reached the cerebrospinal canal in intravenous treatment, as it 
was safe to introduce directly into the cerebrospinal fluid by 
lumba puncture." 

A Direct Versus a Round-about Route 

Dr. Sachs sets forth the fact that when a metallic substance, 
like arsphenamine, is introduced into the spinal canal it is rapidly 
absorbed into the venous system and asks, if this be true, "why 
not use the venous system at once for the conveyance of this 
metallic substance rather than the round-about route via the 
cerebrospinal canal." 

He also shows that British authors, among them Halliburton, 
have abandoned the use of arsphenamine in locomotor ataxia 
and other late syphilitic < affections through the cerebrospinal 
fluid, because they claim it is fatal both to the syphilitic organism 
and to the patient. 

In his own service at Mt. Sinai, Dr. Sachs observes that he has 
obtained the most satisfactory results "from intravenous injec- 
tions administered on alternate days for a period of three to 
four weeks according to the symptoms presented by the patient, 
and then allowing a period of complete rest or giving weekly 
or semi-weekly injections of salicylate of mercury for a period 
of four to six weeks and then again starting in with the same 
course of arsphenamine injections. Some of the patients have 
received as many as forty or fifty intravenous injections within a 
period of a year or eighteen months. There may be a few men 
who could with impunity give the same number of intraspinal 
injections, but the patient will certainly be none the better for 



130 THE TREATMENT OF SYPHILIS 

them and even the most skillful of the intraspinal injectionists 
have had disagreeable experience to record. " 



Intravenous Method Unsurpassed 

Dr. Sachs is emphatic in his statement that no other specific 
medication has ever been as satisfactory as the intravenous use 
of arsphenamine. Where there is good reason to suspect that 
the symptoms of nervous diseases are due to the specific poison, 
the antisyphilitic medication should be begun as early as possible 
and persisted in as long as possible. 

"In the cases of intense headaches, probably meningeal, in 
some of the earliest forms of specific optic neuritis, in the large 
number of cases of cerebrospinal syphilis with actual nerve palsies 
with moderate paralytic symptoms, with incomplete vesical 
disturbance; in the victims of vascular disease, in arteritis luet- 
ica, and above all, in a rather important group of syphilitic 
epilepsies, intensive intravenous treatment leads not infrequently 
to a cure and very often to a marked improvement in all the 
symptoms. But in this group of cases it is easy for us to realize 
that the morbid process is largely confined to the meninges and 
to the surface of the cortical or spinal tissue, but the spirochete 
can no doubt be reached through vascular channels. 

"A group of purely spastic palsies with very slight sensory 
changes, with little or no vesical disturbance, with much more 
rigidity than paralysis, the group which Erb so well described 
and which is long since recognized as a purely degenerative 
group, yields least to intravenous or to any other forms of anti- 
syphilitic medication. The question of the effective treatment 
is most in doubt when we come to consider the results in loco- 
motor ataxia. The tabetic pains, the crises, the bladder symp- 
toms, and the sexual impotence, may be relieved by antisyphilitic 
medication as we have known them to be relieved by prolonged 
periods of rest, by hydro-therapeutic procedures, by mercurial 
injections, by almost any other method of treatment that has 
from time to time been advocated for the treatment of tabes 
dorsalis." 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 13 1 

A Study of Four Hundred Cases 

Dr. Sachs gives these facts to show why he has pinned his faith 
to the intravenous use of salvarsan, or neosalvarsan, and why he 
has rejected the more dangerous intraspinal method of treatment. 
He refers to an article by his associates, Drs. Kaliski and Strauss, 
on "Syphilis of the Nervous System" (Am. Jour. Sypk, p. 609, 
October, 1918), in which a careful critical study of over four hun- 
dred cases from Sachs service is considered. 

In the treatment of early cerebrospinal syphilis, early tabes 
dorsalis, early cases of Erb's spastic paraplegia and those early 
cases of syphilis without nervous symptoms at all or with very 
persistent cephalalgia presenting biological changes in the spinal 
fluid, they utilize salvarsan or one of its safe substitutes. The 
drug is given intravenously every day or every other day in 
doses of 0.2 to 0.3 gram until a total of from 1 gram to 1.2 grams 
is given within a period of seven days. This intensive treatment 
can be safely kept up, they advise us, for a period of from four to 
eight weeks, nor do they consider it necessary to give the drug 
more than three times a week for more than from four to six 
weeks. On alternate days, deep intramuscular injections of 
bichloride of mercury in doses of I / s grain upwards every second 
or third day, or salicylate of mercury, 1 to 2 grains every fourth 
or fifth day are given. 

In lesions of the gummatous type the authors advise the use 
of the iodides, 30 to 60 grains three times a day, in addition to 
the salvarsan treatment. 

Where the symptoms are not so urgent, as in the more chronic 
cases of cerebrospinal lues and tabes, they give from 0.8 gram to 
1.0 gram of salvarsan each week with or without injections or 
inunctions of mercury. 

In the less urgent cases the intravenous injections are kept 
up from six to eight weeks. At the end of this time, there is a 
rest period of from one to two months. 

Drs. Kaliski and Strauss make another group of more chronic 
cases, especially those with the more persistent type of cerebro- 
spinal lues and tabes, with persistent positive reactions in the 



132 THE TREATMENT OF SYPHILIS 

blood and spinal fluid, and with mild subjective symptoms. 
They administer to patients in this group salvarsan from 0.3 to 
0.4 gram twice a week where feasible, or possibly every fifth 
or sixth day for a period of from six to eight weeks, accompanied 
by salicylate of mercury injections 1 to 2 grains every fifth day 
for two months, or they utilize inunctions. 

In the first group, after the disappearance of the distinctive 
symptoms, they do not believe it necessary to maintain the very 
intensive salvarsan therapy for the full period of eight weeks, 
but treat the patients as they do those in the second group if 
improvement has been satisfactory, and in these cases they give 
salvarsan from not more than twice a week to three times a fort- 
night. 

After the resumption of treatment, following the rest period, 
the next course, they say, must be governed entirely by the nature 
of the symptoms. If there is pain, paresthesias, crises, and blad- 
der and rectal disturbances, they advise a second course of sal- 
varsan intravenously followed by mercury, but they do not ad- 
minister salvarsan oftener than once a week in doses of 0.4 to 
0.5 gram for a course of eight injections. They remark that if 
they use neosalvarsan a third larger dose in every instance is 
given. For the purpose of determination of the condition of 
the spinal fluid in cases treated only intravenously a lumbar 
puncture is performed once or preferably twice during each 
course of treatment. 

Persistence in Treatment Necessary 

Drs. Kaliski and Strauss emphasize the necessity of the per- 
sistence in treatment after the initial few months of intensive 
therapy for from one to two years, with increasingly greater 
intervals between treatments. They suggest that after the ces- 
sation of active symptoms the patient should report from once 
to twice a year for observation and further treatment, because 
many of these persons not only have a lesion of the nervous 
system but a syphilitic aortitis, myocarditis, endo-neuritis, or 
some other condition which needs watching. 

They specify a thkd group in which they place cases of more 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 133 

advanced tabes dorsalis, late cerebrospinal lues, optic nerve 
atrophies, spastic paraplegias, and chronic syphilitic epilepsy. 
Destructive lesions involving one or more extremities and pain 
and crises may be the predominating factors in these conditions, 
and they observe that they can frequently bring about the grad- 
ual abolition of pain and the occasional disappearance of the 
crises. Optic atrophy cannot be cured but occasionally can be 
arrested, although they are not optimistic about this condition. 
Their experience has shown that intravenous therapy aids the 
ataxia of these cases, particularly when used with re-educational 
and other local measures. In this group they administer sal- 
varsan every two weeks or, on occasion, every week, in doses of 
0.4 to 0.5 gram for from two to three months and follow it by 
inunctions or injections of mercury. If ataxia is marked, mer- 
cury by injection must be administered with care and for that 
reason they prefer the inunctions. 

In discussion of the treatment of general paresis, Drs. Kaliski 
and Strauss are of the opinion that so far as the use of salvarsan 
is concerned, they are not yet in position to make a definite state- 
ment on account of the lack of sufficient data and the brief 
period of observation since salvarsan was introduced. They 
have had a variety of results in the treatment of this condition, 
the prognosis of which is uniformly bad, and while there were 
some patients who after treatment have had no relapse for more 
than two years, they have had others in whom the treatment 
was ineffective in bringing about much improvement. Their 
method of treatment is that indicated in the caring for the con- 
ditions in group 1. 

Syphilis shows few Contraindications to Arsphenamine and 

Mercury 

They state there are few contraindications to the use of ar- 
sphenamine and mercury in the treatment of syphilis. Optic 
neuritis is not a contraindication, nor is optic atrophy necessarily 
one, although in the latter condition it must be used with great 
care. Cardiovascular conditions, particularly when accom- 
panied by high blood pressure and renal involvement require 



i 3 4 THE TREATMENT OF SYPHILIS 

great care in dosage and frequency of treatment. They remark 
that the prime determining factor concerning the possibility of 
arsphenamine treatment is the integrity of the kidneys and they 
recommend very careful urinary examinations. They say that 
"it is not always necessary to avoid salvarsan therapy because 
of the presence of a mild nephritis, but where treatment is given 
the dosage should be conservative and the frequency of the ad- 
ministration of the drug such as to permit elimination of most 
of the arsenic before the second injection is given." They do not 
give salvarsan more than once in two weeks in these conditions. 
They also note that certain persons have a hypersensitiveness 
to arsphenamine, a phenomenon which usually makes itself 
manifest after two or three injections. They think the patient 
has been sensitized by the previous injections, and that the re- 
actions are due to the toxic action of the drug on the vasomotor 
system. They point out as the first signs of the anaphylactoid 
reaction slight dilatation of the vessels of the conjunctivae or skin, 
feeling of warmth in the face, tickling in the throat, desire to 
cough, slight abdominal rumblings or cramps, feeling of fullness 
in the head, or difficulty in breathing deeply. They advocate the 
suspension of the injection without the withdrawal of the needle. 
If the symptoms are progressive, they believe in discontinuing 
the injection but, if they rapidly pass, they advise the injection 
of a few more c. c. in solution and finally if no untoward results 
follow, the injection of the entire amount. At the time of sub- 
sequent injections they recommend giving these patients 10 or 
15 minims of a 1:1000 solution of adrenalin subcutaneously or 
1/100 grain of atropin sulphate fifteen minutes before the ar- 
sphenamine injection. 

Intravenous First, Intraspinal Later 

Dr. Richard W. Harvey of the University of California (Am. 
Jour. Syph., p. 785, 1918) in a study of cases which have come 
under his care at the University Hospital, San Francisco, be- 
lieves that intravenous arsenic preparations are to be employed 
first in all cases of nervous system lues, accompanied by intra- 
muscular injections of mercury, either the benzoate or salicylate, 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 135 

or, if the patient is in the hospital, by daily inunctions. Intra- 
spinal treatment should be given only after the conservative 
treatment has been employed and then only for the relief of pain 
and of crises in tabes and cerebrospinal lues. 

Intra-Arterial Injection of Neosalvarsan in Cerebrospinal 

Syphilis 

Dr. David A. Sinclair of New York while of the belief that 
salvarsan is the most powerful spirocheticide known, feels that 
its beneficial action in the more serious affections of the cere- 
brospinal system has not been demonstrated. {Med. Times, 
Vol. XLV, No. 1 and No. 4, pp. 18-89, I 9 I 7-) His belief is based 
on the difficulty of bringing the spirochetes in the perivascular 
tissues of the brain and spinal cord into close contact with the 
arsphenamine introduced by ordinary methods. 

A careful study of the anatomy of the brain and the arrange- 
ment of the blood supply, he says, shows this: the common 
carotid artery divides into the internal and external carotids. 
The internal ascends directly to the brain and gives off no 
branches until it enters the skull. With its fellow of the opposite 
side and the two vertebral arteries, the circle of Willis is formed 
through the anterior and posterior communicating arteries. 
Through this media the brain receives its blood supply. The 
choroid artery, a branch of the internal carotid, supplies the 
choroid plexus of the brain, which plexus secretes the cere- 
brospinal fluid. 

Dr. Sinclair's contention is that the injection of neosalvarsan 
into the internal carotid artery is at once distributed to the brain 
and at the same time directly feeds the secretory apparatus of the 
cerebrospinal fluid through the choroid artery. 

The articles quoted from the Medical Times give the history 
of a case in which Dr. Sinclair, after some animal experimenta- 
tion, carried out his belief by injecting five and one-half deci- 
grams of neosalvarsan into the internal carotid artery in a pa- 
tient suffering from cerebrospinal syphilis. This man had pre- 
viously been given intravenous injections of neosalvarsan on 



136 THE TREATMENT OF SYPHILIS 

four different occasions without improvement of his mental con- 
dition, which for three years previous had caused him to act in an 
extraordinary manner. Under ether anesthesia, Dr. Sinclair 
opened the tissues of the neck in the left carotid line and sep- 
arated the internal carotid artery from the jugular vein by pass- 
ing a grooved director underneath it. A small hypodermic 
needle was introduced into the lumen of the artery, the syringe 
attached to the needle, and the neosalvarsan injected. The 
wound was closed by chromicized catgut and silkworm gut 
sutures, a compress placed over the line of incision and all held 
in place by a bandage. The man's condition improved to a very 
considerable extent. Five weeks later the operation was re- 
peated and nine decigrams of neosalvarsan in 10 c. c. of distilled 
water were infused into the right internal carotid artery by the 
same procedure. Twenty-seven days thereafter nine decigrams 
of neosalvarsan in 10 c. c. of water were given in the left carotid 
artery. After that there was marked improvement in the man's 
mental and physical condition. 

Dr. Sinclair is of the belief that therapeutic medication through 
the arterial system offers many opportunities. As an example, 
he mentions a rebellious syphilis of the extremities. He believes 
that the brachial or femoral arteries could be utilized as direct 
carriers of therapeutic agents and thus the consequent dilution 
which must occur when the intravenous route is used would be 
avoided. 

Intracranial Salvarsan Injection 

The intracranial method of the introduction of salvarsan is 
a favorite with some practitioners. The injection is either intra- 
ventricular or subdural. 

After four years of this form of treatment, Drs. H. A. Cotton 
and W. W. Stevenson of the New Jersey State Hospital, Trenton, 
report {Jour. Merit. & Nerv. Dis., 1918) that the intracranial 
method is the most efficacious mode of treatment of paresis, and 
should be the method of preference, while the intraspinal method 
is the most efficient one for the treatment of tabes and luetic 
meningitis. They express the belief that salvarsan is the best 



TREATMENT OF SYPHILIS OF CENTRAL NERVOUS SYSTEM 137 

drug for the treatment of cerebrospinal syphilis and is preferable 
to the substitutes. They urge that the disease should be di- 
agnosed in the pre-paretic stage, or as soon as the symptoms are 
present, and that there should be a frequent examination of the 
spinal fluid in every case of syphilis after all symptoms of the 
acute stage are lost, especially if the Wassermann remains 
positive after sufficient treatment has been given. 

Arrest and Possible Cure of Paresis 

They conclude that all cases of paresis can be arrested and 
possibly cured if the treatment is begun early enough. 

Drs. Walker and Haller (Arch. Int. Med., Sept., 1916) after a 
study of seventy-five cases reach the conclusion that patients 
with recent syphilitic meningitis and cerebrospinal syphilis may 
be relieved symptomatically by intravenous injections of sal- 
varsan. The spinal fluid reaction may become negative with 
1 c. c. and the cell count may become normal. Long standing 
cases of cerebrospinal syphilis and tabes are likely to be sympto- 
matically benefited by salvarsan but they think there is little or 
no change in the spinal fluid findings. 

Patients with recent as well as late syphilitic meningitis, 
cerebrospinal syphilis, tabes, and general paresis are markedly 
improved following intravenous salvarsan and intraspinal sal- 
varsanized serum, and those who fail to improve under one do 
improve under the combined treatment. 

Permeability of the Meninges to Arsenic in Paresis and Tabes 

In patients who have received intravenous injections of sal- 
varsan or neosalvarsan it has been demonstrated that the serum 
contains more than five times as much arsenic as the clot. Within 
thirty minutes, about 75 per cent of the salvarsan is fixed in the 
body cells and 24 hours after the intravenous administration of 
salvarsan, it is found that arsenic has passed into the spinal 
fluid. 

When serum treatment is used, it is readily observed that a 
soluble arsenic preparation formed from the body cells is being 



138 THE TREATMENT OF SYPHILIS 

administered. This preparation contains the larger amount of 
the arsenic which remains in the circulatory system. It also 
suggests the need of drawing the blood during the first thirty 
minutes after the intravenous administration of the drug when 
it is to be used as a source of serum containing arsenic. 



CHAPTER XIII 

THE TREATMENT OF CONGENITAL, MALIGNANT AND VISCERAL 

SYPHILIS 

Congenital Syphilis 

Various plans for the treatment of congenital syphilis are in 
vogue, and most syphilologists have their own methods of 
procedure. 

A logical plan has been devised by Eugene Graetzer and is de- 
scribed {Urol. 6 s Cut. Rev., September, 1916) as a course or a series 
of courses of neosalvarsan and calomel. 

A single course consists either of 12 calomel and 8 neosal- 
varsan injections, or of six weekly inunctions and eight neosal- 
varsan injections. The courses occupy approximately a period 
of three months. 

The combined calomel-neosalvarsan course is applied accord- 
ing to the following scheme: 



Week 


Treatment 


1 ' 

2 

3 




Two calomel injections. 
1st and 2nd neosalvarsan injections. 




4 
5, 




3rd and 4th calomel injections. 
3rd and 4th neosalvarsan injections. 




O 

7 
8 


5th and 6th calomel injections. 
5th and 6th neosalvarsan injections. 




9 
10 
11 


7 th and 8th calomel injections. 
7th and 8th neosalvarsan injections. 




13 
14 


9th and 10th calomel injections, 
nth and 12th calomel injections. 





140 



THE TREATMENT OF SYPHILIS 



Following this first course there comes a rest for three months, 
after which the second course begins in the same way; and, after 
a second rest for three months, the third course in the same pro- 
portions takes place. The combined inunction and neosalvarsan 
cure is applied as follows : 



Week 


Treatment 


i 

2 

3 


Inunction course (i week). 

ist and 2nd neosalvarsan injections. 

Inunction course (2 weeks). 


4 
5 
6 

7 
8 


3rd and 4th neosalvarsan injections. 


Inunction course (3 weeks). 

5 th and 6th neosalvarsan injections. 


9 

IO 

ii 


Inunction course (4 weeks). 

7th and 8th neosalvarsan injections. 


13 
14 


Inunction course (5 and 6 weeks). 



From the second year on, calomel and inunctions are alternated. 
In infancy, because of the small surface and the sensitiveness of 
the skin, it is better to avoid inunctions. Dosage, according to 
Graetzer, is as follows: 0.001 g. calomel and 0.015 K- neosalvar- 
san per kilogram of body weight. Of course, the first injection 
of neosalvarsan is less than given in the scale in order that idiosyn- 
crasies may be ascertained. The author has never observed any. 

As a site for injecting the calomel and also for the epifascial 
injections of neosalvarsan, he recommends the thick musculature 
of the nates in the upper external quadrant. The calomel in- 
jections can also be injected into the upper limb. The neosalvar- 
san is usually applied intravenously in infants, either into the 
veins of the skull, the ankle-joint, the jugular, or recently, ac- 
cording to L. Tobler, into the sinus longitudinalis. This last 
mentioned method proved to be very satisfactory, but it is a 
hospital procedure which limits its field of usefulness. Only in 



CONGENITAL, MALIGNANT AND VISCERAL SYPHILIS 141 

exceptional cases should infants receive neosalvarsan injections 
intramuscularly. The author keeps on hand, 3, 4, 5 per cent 
solutions of calomel in olive oil. With large children he uses pref- 
erably the 40 per cent calomel solution of Zichler. 

He says "the dosage of the grey ointment for the inunction 
course is at the rate of 1.0 grm. of ointment to 10 kg. body weight 
and should not exceed 4.0 g. A child weighing 20 kg. gets six 
inunctions of 2 g. per week and on the 7th day is bathed." 

Treatment of the Expectant Mother 

Many men favor treatment of the expectant mother, if she or 
her husband be syphilitic, in the hope of preventing a luetic 
child. This plan consists of intensive treatment with salvarsan 
or neosalvarsan, mercurial inunctions and the iodides. 

Dr. Lisser {Cat. State Jour. Med) believes it to be wiser, if the 
treatment is begun during the early months of pregnancy, to 
employ frequent small doses of salvarsan, 0.2 to 0.3 to 0.4 gram, 
rather than the full dose, although it has been shown that sal- 
varsan does not seem to increase the tendency to abortion or 
hemorrhage. But the total amount of salvarsan should be at 
least 1.5 grm., and larger amounts are safer. 

Such treatment affects the fetus favorably by its curative 
action on the mother, and in the early stages especially, by pre- 
venting disease of the placenta. Furthermore, Meyer has shown 
in the case of salvarsan, that whereas a normal, sound placenta 
does not allow arsenic to permeate, the syphilitic placenta does 
permit the drug to pass through to the fetus. 

Findlay and Robertson {Glasgow Medical Journal) record 
several successful examples of such antenatal therapy. "In no 
case was the course of the pregnancy interrupted, and the mothers 
did not seem to suffer much from the treatment. The mothers, 
as a rule, expressed themselves as feeling better during these than 
during any of their previous pregnancies. " 

So far as their experience goes, equally good results were 
obtained whether treatment was commenced as early as the 
second month or delayed the seventh month of pregnancy. ' ' This 
in all probability is to be accounted for by the fact that many 



142 THE TREATMENT OF SYPHILIS 

syphilitic infants are infected during parturition, the mischief 
remaining local in the placenta during the whole course of ges- 
tation. It is this uterine localization of the disease which ac- 
counts for the absence of clinical manifestations in many of the 
mothers of syphilitic children. Baisch, Trinchese, and Weber 
working in Doderlein's clinic, found that in the case of every 
syphilitic child the placenta, both the fetal and maternal por- 
tions, contained spirochetes, and in common with Rietschel are 
inclined to the opinion that the spirochete always travels to the 
child from the placenta. 

"Most authorities agree that during gestation the spirochete 
may travel along the umbilical cord and infect the fetus, but 
this according to Rietschel is less frequent than infection by 
emboli set free during parturition. It would therefore seem ex- 
ceedingly likely that in the treatment of pregnant women the 
salvarsan gets easily at the very vascular placenta and destroys 
the contagium vivum, thus considerably lessening the risk of 
embolism from living spirochetes." 

Antenatal Treatment Versus no Therapy 

It is interesting to compare the statistics of such antenatal 
therapy with the results of no therapy at all. With no treatment 
of maternal syphilis at all, the primary mortality of congenital 
syphilis is enormous. In the first year of life, Leduc estimates 
it at 71 per cent; Zeissl at 80 per cent; Bunch at 90 per cent; 
Markus at 90 per cent. Hochsinger claims that 93 per cent, of 
syphilitic children have disease of the nervous system. 

According to Galliot, when mothers are treated before preg- 
nancy, but not during pregnancy, 82 per cent of the resulting 
children are born dead. 

Mercurial treatment of the pregnant mother has the following 
results to commend it: Of 217 infected pregnant women showing 
signs of active syphilis during their pregnancy, who were vigor- 
ously treated with mercury and iodides during their pregnancy, 
25 per cent of the resulting progeny were born alive, of whom 
10 per cent showed signs of syphilis. This is at once a striking 
improvement over no treatment at all. 



CONGENITAL, MALIGNANT AND VISCERAL SYPHILIS 143 

Of 163 pregnant infected women, without signs of active lues, 
but having so-called latent lues, who likewise were vigorously- 
treated with mercury and iodides during their pregnancy, 66 
per cent living children were born who were well clinically; 14 
per cent were born alive but showed signs of congenital lues, and 
19 per cent were born dead. Pinard, Champetier de Ribes, and 
Potocki, by prolonged treatment with mercury and potassium 
iodid, obtained 76 per cent of the children healthy. 

Of 128 women with latent lues, who were treated before and 
during pregnancy with mercury and iodides, 88 per cent living 
children, clinically well resulted, the remainder showing signs of 
syphilis. These statistics are surely a strong argument in favor 
of the thorough treatment of the disease (Galliot). 

Fleeting Character of Mercury 

But the effect of mercury unless continued is fleeting. This 
is illustrated in an astonishing manner by the following case 
reported by Fournier (Meyer). A syphilitic woman was preg- 
nant eleven times. She had no treatment whatsoever during 
the first seven pregnancies, and the result was seven dead luetic 
children. During the eighth and ninth pregnancies, energetic 
mercurial treatment was given, and the result was two healthy 
children. No treatment was taken during the tenth pregnancy 
and again a luetic child was born dead. Treatment during the 
eleventh pregnancy was successful in bringing forth a healthy 
child. Fournier concludes: "So powerful yet so fleeting is the 
effect of mercury that, if it were not immoral, I would like to 
try the experiment of alternately treating and not treating a 
syphilitic mother, and alternately bringing into the world healthy 
and syphilitic children." 

Advantages of Salvarsan 

When salvarsan was combined with such mercurial therapy, 
remarkable results were obtained, Sauvage reporting 93 per cent 
and Bourret and Fabre 100 per cent cures. These latter statis- 
tics may be somewhat enthusiastic, for it must be admitted 
that many cases, showing congenital syphilis after reaching 6 to 



144 THE TREATMENT OF SYPHILIS 

20 years of age, showed no specific manifestations whatsoever 
during the first few years of life. Most of the cases reported 
were only observed during the first few months or first year of 
life, and are therefore subject to this reservation. Nevertheless, 
it would seem that this method of antenatal therapy has much to 
support it and merits extensive trial. 

Dr. Lisser notes that another prophylactic measure suggests 
itself. Suppose that an apparently healthy child, with negative 
Wassermann and negative luetin, is born from parents known to 
have active syphilis. In view of the fact above-mentioned, that 
luetic stigmata do not develop in certain cases until long after 
infancy, would it not be prudent to administer small doses of 
mercury intermittently to such a child during the first few years 
of life? In reasonable quantities such therapy would not be 
harmful. It might be beneficial. It is almost impossible to bring 
facts or statistics in favor of such a procedure, for the unanswer- 
able criticism can always be advanced that the particular child 
so treated may never have developed syphilis anyway. But 
when one bears in mind the extraordinary obstinacy of just 
those cases where the disease makes its appearance late in child- 
hood, it would at least appear to be an error on the side of safety 
to treat prophylactically infants who are the progeny of parents 
recently tainted with syphilis. 

Old salvarsan, unfortunately, has not the wide application in 
congenital syphilis that it has in the acquired form, Dr. Lisser 
goes on to say, not because it is less efficacious, but because of the 
difiiculties of administration. Even in acquired syphilis its 
intramuscular use has been largely abandoned, the pain resulting 
from the injection and the necrosis and sloughing that not in- 
frequently supervene are very serious objections; and in children 
the delicacy of the tissues should absolutely prohibit its use in 
this way. However, salvarsan can and should be used intraven- 
ously whenever there is a vein of sufficient size at the bend of the 
elbow. It should be well diluted and the consequent large amount 
of fluid to be injected must be allowed to flow into a vein in a 
position where the flow can be easily controlled. 

The jugular vein has been used and likewise the veins of the 



CONGENITAL, MALIGNANT AND VISCERAL SYPHILIS 145 

scalp, but whereas these routes are excellent in the case of neo- 
salvarsan where highly concentrated solutions can be used and 
the operation quickly finished, it is difficult to keep the child 
quiet enough for a sufficiently long period of time to permit the 
steady flow of 50 to 100 c. c. as is the case when salvarsan is used. 
In view of the frequency of these injections it does not seem ad- 
visable to anesthetize the child, particularly when other effica- 
cious drugs are available. Salvarsan should only be given in- 
travenously, and only into a vein of the forearm. Its dosage 
must be regulated according to the age and size of the patient, 
and the first dose should always be exceedingly small. Even in 
the adult, there is a growing tendency to use smaller individual 
doses, especially the initial dose; that is from 0.2 to 0.4 gram in- 
stead of 0.6 gram. It is evident that much greater caution is 
necessary in young children; 0.01 gram to every kilo, or 2^ 
lbs., is a safe average. It is probably a safe custom to place such 
children in a hospital over night. Lisser believes that in the com- 
paratively few cases where salvarsan can be used, the results are 
highly satisfactory. Just as in acquired lues, mercury should 
invariably be used in combination with the salvarsan. Neither 
alone is as reliable as both together. 

A Wider Field for Neosalvarsan 

Neosalvarsan has a wider field of usefulness in congenital 
syphilis than in the acquired form, Lisser observes, and for the 
following reasons: Its use in acquired lues is largely a matter of 
convenience, and can be entirely displaced and should be dis- 
placed by the more powerful effect of old salvarsan. But in 
inherited lues it is invaluable because of the high concentration 
in which it may be injected. 

It can be employed in two ways: first, intravenously, using the 
veins of the scalp, as first suggested by Neogarrath in 191 1. 
This is the method of choice in infants up to about two years of 
age. Simpson and Thatcher in 1913 advocated the use of the 
external jugular, but, in the technic they describe, an anesthetic 
is necessary, the vein being cut down upon and a cannula in- 
serted. Such a drastic procedure was justified at the time when 



146 THE TREATMENT OF SYPHILIS 

it was thought that one large dose would cure the disease, but 
since experience has demonstrated the necessity of frequently 
repeated injections, it would be wiser to use other methods at 
our disposal. By utilizing the veins of the scalp, neosalvarsan 
can be given in 3 or 4 c. c. of saline or freshly distilled water in an 
ordinary Record or Luer syringe, and in a very few minutes. The 
initial dose should be calculated from 0.015 gram per kilo; that is 
about 0.05 gram for a new-born infant, gradually increasing in 
successive doses to 0.2 or even 0.3 gram per injection. This 
dosage has been used with safety and success. Slight reactions 
such as vomiting, diarrhea, and occasionally fever will result, but 
no more so and no more serious than occurs frequently in adults. 

Epifascial Method of Injection 

Wechselmann's so-called epifascial method of injection is 
serviceable in those children between the ages of 2 and 7, who 
have neither veins of the scalp for intravenous neosalvarsan 
nor veins of the forearm for old salvarsan. Wechselmann em- 
ploys it in his routine treatment of adults, never giving neosal- 
varsan intravenously, but only epifascially, and reserving the 
veins for old salvarsan. The technic requires some practice, but 
once learned, is really very simple, quick, and convenient. 

Mercury is as valuable in the treatment of inherited syphilis 
as salvarsan. To omit its use would be an error. The official blue 
ointment may be used. The skin of children will not permit 
vigorous rubbing nor is it necessary. Inunctions should be given 
six days out of the week. In very small children and infants 
bichlorid baths are very satisfactory. Twenty or thirty grains 
of bichlorid mixed with an equal quantity of ammonium chloride 
should be used. 

Oral medication is not satisfactory for several reasons. Ab- 
sorption from the intestinal tract is uncertain and if the parent is 
in charge of the treatment, doses may be given irregularly, and 
when taken faithfully derangements of the intestinal tract are 
not uncommon. The gray powder, mercury with chalk, in doses 
of %-yi gr., or calomel gr. 1/10-1/4 t. i. d., is probably as good 
as any of the many preparations. 



CONGENITAL, MALIGNANT AND VISCERAL SYPHILIS 147 

The Value of the Iodides 

Lisser insists that the iodides occupy an important place in the 
specific therapy of congenital syphilis. They should be given 
far more frequently than is generally the case, and their mode of 
action and precise value should be more clearly appreciated. 
The iodides should never be given without mercury or salvarsan. 
The destruction of the causative organism is accomplished by 
the mercury and salvarsan, but the wreckage that results is 
swept away by the iodides. They occupy a singular role, there- 
fore, in supporting and completing the work of the destroyers. 
The function of the iodides is to dissolve and eliminate. Although 
their most spectacular efficiency is demonstrated in the tertiary 
processes where gummas are magically made to vanish under 
their influence, they should likewise be used in the earlier stages 
of the disease, for the principle of their action remains the same, 
and it is at all times beneficial to aid in the elimination of the 
syphilitic poison. 

The two commonest preparations of the iodides are the sat- 
urated solution and the combination in liquid form with mercury 
in the so-called "mixed treatment." When exceptional cir- 
cumstances demand the use of mercury by mouth, this mixed 
treatment is quite satisfactory. It must be remembered that 
only the bichlorid or biniodid should be used in such a mix- 
ture, for the proto salts are changed by the iodides into the 
binary forms, making a more powerful and perhaps dangerously 
high dosage. If mercury is given in pill form, it should be taken 
an hour before meals, and the potassium iodid an hour after 
meals, so that the former will have left the stomach before the 
latter arrives. 

As a routine preparation the saturated solution is very satis- 
factory. It should always be given in high dilutions, preferably 
in a large glass of milk, always after meals, as it irritates an 
empty stomach, and in much higher dosage than is generally 
prescribed. The usual dosage for adults will not be high for little 
children, namely 30-45 grains per day, and it is far too low for 
adults. Probably little good is accomplished in adults under 



148 THE TREATMENT OF SYPHILIS 

75 grains per day, and many cases require several hundred 
grains per day. So for children an initial dose of 5 grains t. i. d. is 
quite conservative and should be rapidly increased. Iodism is 
more common with small doses of potassium iodid than with 
enormous doses. 

Malignant Syphilis 

Arsphenamine plays the leading role in the treatment of this 
condition, which is characterized by rapid destruction of tissue, 
following marked skin ulcerations and results in the permanent 
formation of gummata. The process attacks chiefly the scalp, 
face and limbs, may affect the oral cavity and sometimes leads to 
bone necrosis. 

A marked characteristic of malignant syphilis is intolerance to 
mercurial treatment. Patients easily become salivated and the 
drug is practically contraindicated, particularly during the early 
stages of the disease. 

Salvarsan is usually well borne and has proved very effective. 
Its use as a spirocheticide is the one bright and shining feature in 
the treatment of this severe condition, and potassium iodid should 
be employed in heroic doses to aid in the absorption of gum- 
matous infiltrations. 

The hygiene of these patients must be watched carefully and 
they must have every advantage. The diet should be nourishing 
and stimulating, tonics such as quinin and iron are to be adminis- 
tered, and sea water bathing is advised. In addition the patient 
must live in the open air. 

The local treatment of the ulcers consists in bathing with 
potassium permanganate or some equally efficient non-toxic 
disinfectant and dusting the sores with a pure, bland powder. 

Proper hygiene, salvarsan and potassium iodid will usually 
prove effective in malignant syphilis. 

Tertiary Lesions of the Viscera 

When syphilis has invaded the vital organs of the body as 
the result of insufficient or improper treatment, in the form of 
syphilitic endarteritis, periarteritis and infiltration, vigorous 






CONGENITAL, MALIGNANT AND VISCERAL SYPHILIS 149 

treatment must be instituted to kill the treponemata and absorp 
the infiltrations. 

The method of procedure in these cases, according to Dr. 
Harlow Brooks of New York (AT*. Y. State Jour. Med., April 15, 
1916), should differ from the usual routine. 

The treatment of syphilitic aortitis, aneurism and heart con- 
ditions includes at first several intramuscular injections of salicy- 
late of mercury. Then intravenous injections of salvarsan may 
follow, the first being 0.3 gram and the dose is to be increased 
if no untoward results ensue. The course of treatment is con- 
cluded by the employment of potassium iodid in increasing doses. 

The purpose of the iodid is to absorp the newly formed gum- 
matous tissue. 

Especial attention is directed to the necessity of using mer- 
cury for several weeks before commencing the arsphenamine 
treatment. 



CHAPTER XIV 

SYPHILITIC RE-INFECTION 

The impression is becoming more and more firmly established 
that there is no such thing as a general natural immunity from 
syphilis. The one-time belief that one syphilitic infection brought 
about immunity from further infection has been broken down 
by cases of actual re-infection which have come to the attention 
of the great bulk of the syphilologists of this country from 
time to time. 

The treatment of syphilis by means of salvarsan has un- 
doubtedly had some effect in this connection. Under the old 
method of treatment it is probable that a great number of the 
so-called cured cases of syphilis were not cured. When one of 
those uncured cases showed luetic symptoms the second time it 
was doubtless an outbreak of the original condition. For this 
reason cases of re-infection were so very exceptional that the 
profession had good reason to believe that there was no such thing 
as re-infection. 

We now believe that syphilis properly treated can be cured, 
and it is very apparent that re-infection does not take place 
until the initial infection has been absolutely cured. 

A considerable number of cases of re-infection have been re- 
ported in medical literature during the last few years. General 
acceptance of these conditions enables the physician to judge as 
to positive proof of re-infection, if spirochete are found in a 
new chancre appearing in a different site from the original lesion 
and if the blood gives a negative Wassermann reaction. This, of 
course, is predicated upon the attack being seen shortly after 
the appearance of a lesion as well as upon the discovery in the 
first attack of the spirochete with all the presence of syphilitic 
lesions, such as the rash, mucous patches, or condylomata, or a 
positive Wassermann reaction which has not been the result of 
hereditary syphilis. 



SYPHILITIC RE-INFECTION 151 

Major C. F. White, R. A. M. C, reports (Brit. Med. Jour., 
Oct. 20, 191 7) a series of cases in which the first attack was treated 
with salvarsan and mercury and a cure effected, in his belief. 
At a later period there was what seemed to be a re-infection, 
living up to the conditions heretofore mentioned, and these were 
treated with salvarsan and mercury and, to the best of his belief, 
also were cured. 

He also reports another series in which the second attack did 
not live up to the bacteriological findings and the necessary 
serum tests, but he believes them, nevertheless, to have been 
cases of re-infection, as each one of these cases had been seen by 
him during both the attacks. 

In the treatment of 10,500 cases of syphilis in two years, Lt. 
Col. Harrison saw 28 cases of re-infection. Additional cases 
could be quoted but these will suffice to show the physician that 
he must bear the possibility of re-infection in mind in the treat- 
ment of various cases of syphilis. 



CHAPTER XV 



THE CUKE OF SYPHILIS 



The day has not yet arrived for any clinician to attempt to 
establish a definite standard of cure of syphilis. The old method, 
in which the physician gave mercury and iodides over a period of 
years and then pronounced the cases cured, has been relegated to 
the discard. Sufficient time has not elapsed since the introduc- 
tion of 606 to permit us to have an absolute knowledge as to the 
lasting effects of arsphenamine upon the spirocheta pallida. The 
spirochete may have resting periods; it may possess arsenical 
tolerance, particularly when we know that cases, which seem to 
have been arrested, if not cured, still continue positive. We 
believe that eternal vigilance is necessary in the consideration of a 
"cure" and, as elsewhere expressed, we should for a period of 
years follow up these cases and watch them carefully through the 
eyes of the Wassermann reaction. 

The Standard of Cure of Syphilis 

Oswald Dinnick, of the Royal Free Hospital of London (Lan- 
cet, June 21, 1 91 9) in an instructive lecture before the London 
School of Medicine for Women, set forth as his belief that if, 
after an intensive course of arsenical medication and the con- 
tinuous exhibition of mercury for two years, a patient can show 
two years' freedom from physical signs of disease, has a per- 
sistently negative blood serum, a spinal fluid which shows no 
variation from normal in either pressure, globulin content, or 
cellular count, and which gives a negative Wassermann in 
amounts of 2 c. cm. ; and, if after a period of freedom from treat- 
ment, these conditions are still present and persist in spite of 
provocative treatment, it is justifiable, in our present state of 
knowledge, to presume this patient cured. 



THE CURE OF SYPHILIS 153 

Finally, should this patient subsequently develop a fresh 
chancre, at a site differing from the first, this would be a re- 
infection, and would prove our contention. For syphilis does not 
confer immunity, and the real interpretation of all alleged im- 
munity is that the so-called immune person is an active syphilitic. 

Wechselmann, in his Saharsan Therapy, Volume 2, page no, 
sets forth conditions of cure which are accepted by many persons 
as authority. According to him, cure is effected when the patient 
is free from symptoms of the skin, mucous membrane, and all 
inner organs; when his blood serum no longer shows a positive 
Wassermann reaction; when his lumbar puncture shows no al- 
terations, and if this absence of all positive signs, especially the 
negative Wassermann and the negative lumbar puncture, remains 
permanent upon most careful control for a certain period of time. 

Wechselmann says that this particular period is generally ac- 
cepted as one year, although this is not absolute. He advises the 
taking of the blood for the Wassermann at from two to four- 
month intervals and that a spinal puncture should be made at 
less frequent intervals. 

We believe that Wechselmann's time limit is too short and 
are much more inclined to accept Dinnick's views that the pa- 
tient should show two years' freedom from physical and serologi- 
cal signs. 

Prevention of Infection of the Operator 

Some physicians exercise little or no precaution against in- 
fecting themselves while administering arsphenamine and neo- 
arsphenamine. 

It must be borne in mind that the blood of all syphilitics is 
infectious, that of persons in the primary and secondary stages 
being more capable of conveying the infection than that in 
tertiary and latent stages. 

It is agreed that the chancre and the mucous patch are much 
more fertile fields of infection than the blood, but as all these 
sources readily transmit the treponemata, the physician should 
protect his hands with rubber gloves and as a double precaution 



154 THE TREATMENT OF SYPHILIS 

he should employ collodion about the finger nails in the event of 
the presence of a hang nail or an abrasion. 

Penetration of the operator's hand or finger by a used salvar- 
san needle should be followed by an immediate laying open on the 
part, after first shutting off the blood supply, and the application 
of pure phenol. The introduction of an injection of arephenamine 
or neoarsphenamine is also advisable on account of its prophy- 
lactic action, as elsewhere set forth. 



The Care of Arsphenamine Needles 

Niceties in technic in arsphenamine administration are essen- 
tial. Little matters of detail may cause a change from trouble to 
comfort. Arsphenamine needles need as much care as the other 
parts of salvarsan's administrative apparatus, but they are too 
often neglected. A glance through the bore of a used needle 
will likely reveal a dirty lumen and the residue in the bore when 
examined will be found to be a black mass of unknown composi- 
tion, which has no place in any aseptic operation. 

The writer has kept needles clean by the use of a good metal 
polish and a copper wire a little larger than the stylet accompany- 
ing the needle. The wire should fit the bore of the needle closely. 
Part of the wire is dipped in the metal polish and is drawn back 
and forth through the needle several times. If the wire is then 
wiped off on a piece of gauze a black deposit will be observed. 

The clean wire is again immersed in the metal polish and the 
operation is repeated until no deposit is left on the gauze. The 
bore of the needle should be as clean as the bore of a rifle. 

After administering salvarsan it is our custom to boil the 
needle, run alcohol through it and then cover it with I D L, an 
Irish moss preparation, which prevents rusting. It may also 
be kept in oil. 

Arsphenamine needles must be very sharp, with a short bev- 
elled edge, to prevent wounding of the vein. We formerly sent 
needles to an instrument maker to be sharpened, but of late have 
personally utilized a piece of carborundum for the purpose. By 
so doing the physician can always have a sharp needle at his 



THE CURE OF SYPHILIS 155 

command, with the kind of point which his experience demon- 
strates is best. 

In a discussion of the care of needles, the type of needle may be 
mentioned. 

A number of syphilologists have had special needles made 
embodying ideas of their own, but most physicians use the needle 
they first employed when giving intravenous injections. 

After trying the various types on the market, we have adopted 
the Fordyce and use it exclusively. 

Its particular advantage is the shank, which enables the 
operator to obtain such a firm grasp that no sudden movement 
on the part of the patient can shake it out of his hand. 

This shank also permits the physician to pursue a rolling, elu- 
sive vein, which may not have been properly fixed between the 
thumb and forefinger of the other hand, without making a second 
entrance through the skin. 

Hygiene for Syphilitic Patients 

No alcoholic liquors should be ingested. 

The use of tobacco, either by smoking or chewing, aggravates 
those cases in which mucous patches are present in the mouth. 

Tepid baths should be taken daily, if no eruption be present, 
followed by a brisk rub. A hot bath should be taken every two 
or three days. Sometimes a hot water shower, followed by a cold 
one, is of benefit. Turkish baths may be taken once or twice a 
week, if no active skin troubles are present. 

The teeth should be brushed in the morning, after meals, and 
upon retiring, and a cleansing mouth wash will add to the 
patient's comfort. 

The patient should sleep alone. 

He should use his own dishes and table cutlery, towels, tooth 
brush, brushes, combs, shaving utensils, pencils, scissors, etc. 

He should kiss no one and sexual intercourse is strictly in- 
terdicted for the first year of the disease or during a relapse. 

During the presence of oral mucous patches he should keep his 
fingers out of his mouth and be particular that his saliva does 
not come in contact with any one or with anything in use. 



156 THE TREATMENT OF SYPHILIS 

He should wash his hands very frequently and always after 
touching his genitals. 

Dietary for Syphilitic Patients 

In the treatment of lues it should be remembered that the 
patient is suffering from a constitutional disease, that he demands 
special food and that his particular symptoms necessitate treat- 
ment as they arise. 

The following dietary is suggested: 

The Patient Can Have 
Soups, all except tomato. 

Fish. — All fresh fish, boiled, baked, or broiled. Raw oysters, 
scallops, lobsters and clams. 

Meat. — Beef, mutton, roasted, boiled or broiled; poultry; 
game; veal, lamb chops or cutlets; eggs, soft boiled, scrambled, 
poached, raw or in omelettes. 

Farinaceous. — Cracked wheat, oatmeal, mush, sago, tapioca, 
rice, hominy, barley, marcaroni, vermicelli, whole-wheat bread, 
stale or toasted wheat bread, brown bread, milk toast, corn 
bread. 

Vegetables. — Green peas, string beans, parsnips, turnips, 
spinach, cauliflower, mushrooms, celery, lettuce, asparagus, 
sweet potatoes, white potatoes in moderation, preferably baked. 

Desserts. — Custards, rice or cornstarch puddings, blanc mange. 

Drinks. — Water, plain or aerated, cocoa, chocolate, milk, kou- 
miss. A limited amount of coffee may be given when no active 
symptoms are present. 

The Patient Can Not Have 

Any fried foods, or pork cooked in any way. 

Any sour, acid, spicy or peppery foods. 

Any canned, salted, pickled or preserved meat or fish. 

Any alcoholic drinks or tea. 

Any pastry. 



THE CURE OF SYPHILIS i 57 

The patient should be instructed 

To eat animal food at every meal and to eat more animal than 
starchy food. 

When Can the Syphilitic Patient Marry? 

Nearly forty years ago Fournier of Paris, in his Syphilis et 
Mariage, set down these governing rules for the marriage of 
syphilitic patients: 

a. Absence of actual specific lesions. 

b. Advanced age of the infection. 

c. A certain period of absolute immunity. 

d. Non-menacing character of the disease. 

e. Sufficient specific treatment. 

Finger of Vienna in 1896 specified that five years should inter- 
vene between the times of infection and marriage and that three 
years should intervene between the last syphilitic manifesta- 
tion and marriage, there having been systematic treatment of the 
disease, with an energetic course of mercurial treatment preceding 
the marriage ceremony. 

Dr. Joseph Lewi, who for fifty years practiced medicine in 
Albany, N. Y., at a time long before arsphenamine was brought 
to the attention of the medical world, advised as follows: 

"No man or woman ever afflicted with syphilis has a right to 
marry until three years after all symptoms of the disease have 
disappeared. In the meantime and for a period of three years, 
the mixed treatment (one thirty-second o? a grain of corrosive 
sublimate and ten grains of iodid of potassium) should be given 
such patients three times a day for a period of twenty days at 
four different periods of each year." 

Observations, extending over a period of seventy years, of 
cases coming under the care of Dr. Lewi and his sons, who co- 
operated with and succeeded him in practice, show that where 
the treatment was followed as above outlined, the after-effects 
on progeny were limited to cases of premature birth and of abor- 
tions in first and second pregnancies, and that other complica- 
tions were negligible. 



158 THE TREATMENT OF SYPHILIS 

In the light of our present knowledge the physician should not 
give his consent to the marriage of a syphilitic patient until the 
provocative injection, after repeated Wassermanns, of blood and 
spinal fluid have demonstrated that the spirochete have been 
absolutely eliminated from the system. A man with a positive 
Wassermann, even though it be caused by an aortitis or a lesion 
of the spinal cord, should not marry or endeavor to procreate. 



AUTHORITIES QUOTED 



Ballenger, 56 

Barewald, 40 

Barnes, 56 

Binz and Schulz, 27 

Blue, 98 

Bourrett and Fabre, 143 

Brechot, 35 

Bunch, 142 

Burgess, 1 

CoIe ; 32 
Cotton, 136 
Craig, 60, 107 

Danysz, 103 
Danysz and Fleig, 59 
Dinnick, 152 

Ehrlich, n, 25, 62 
Ellis, 114 

Favre and Massia, 73 
Findlay and Robertson, 141 
Finger, 157 
Fischer, 57 
Fordyce, 6, 80, 122 
Fournier, 143, 157 

Galliot, 142 
Gennerich, 105 

Harrison, 65 
Harvey, 134 
Herring, 59 
Hewlett, 104 
Hillman, 1 
Hochsinger, 142 



Jackson, 50, 102 
Jacobsen, 93 

Kaliski and Strauss, 131 
Keyes, E. L., Jr., 56, 101 

Leduc, 142 
Lewi, 157 
Lisser, 141 
Lydston, 33 

Magian, 34 
Markus, 142 
McCoy, 71, 96 
McNeil, 6 
Morton, 8, 31 
Mouneyrat, 22 
Murray, 41 
Myers, 50, 92 

Nichols, 82 

Ogilvie, 119 
O'Leary, 105 
Ormsby, 36 

Pollitzer, 40 

Rohl and Friedberger, 26 
Rothwell, 35 

Sachs, 128 
Sauvage, 143 
Sieburg, 29 
Sinclair, 135 
Smith, M. I., 50, 102 
Smith, T. H., 57 



160 AUTHORITIES QUOTED 

Stevenson, 136 Vedder, 32, 101 

Stokes, 88, 105 

Swift, 114 Wechselmann, 101, 146, 153 

White, 151 
Thomas, 74 

Thompson, 32 Zeissl, 142 

Trimble, 35 



INDEX 



Acute Optic Neuritis and Salvarsan, 

3i 

Administration of Mercury, Technic 
of, 77 

Administration of Salvarsan: 
Bringing out Veins, 55 
Choice of Veins, 52 
Collapse, Use of Tyramine in, 104 
Concentrated Injections, 56 
Danger of Rapid Injections, 55, 96 
Distilled Water in, 54 
Epinephrin, Use of, 88, 134 
Examination of Urine, 31, 52 
Fordyce Technic, The, 123 
Helpful Hints in, 54 
Into Superior Longitudinal Sinus, 

57 
Intracranial Injections, 136 
Intraspinal Treatment, 120 
Introduction of Needle, 53 
Necessity of Slow Injections, 54 
Preparation of Patient, 52 
Subarachnoid Injections, 115 
Swift-Ellis Method, 114 
Use of Vasodilators in, 56 
"Windows" over Vein, 56 

Amboceptor, 2 

Ammonium Iodid, 10 

Antenatal Treatment, 142 

Antibodies, 3 

Antigens, 3 

Antiluetic Agents, 10 

Antiluetic Treatment, Plan for, 37 

Antiphlogistine after Intramuscular 
Treatment, 66 

Arsacetin, n, 21, 26 



Arsenic, 10 

Arsenic Compounds, Chemotherapy 

of, 25 
Arteries as Carriers of Therapeutic 

Agents, 135 
Arsphenamine: 

Accidents following Use of, 100 

After Treatment following Intra- 
muscular Use, 66 

Alkalinization, Importance of, 46, 
50 

Arsenic Content of, 19 

As an Abortive Agent, 30 

As a Prophylactic, 34 

Apparatus for Administration, 43 

Blood Pressure During Adminis- 
tration, 102 

Chemistry of, n 

Color and Solubility, 19 

Comparative Use with Neoar- 
sphenamine, 35 

Concentration of, 46, 56, 96 

Contraindications to, 30, 133 

Diagrammatic Outline of, 16 

Dilution of, 47, 95 

Discovery of, 12 

Distilled Water for Solution, 44 

Dosage, 37, 85 

Effects of Wassermann Reaction 
on, 106 

History of, n 

Immediate Mother Substance of, 

14 
In Non-leutic Conditions, 34 
Indications for, 30 
Intramuscular Administration, 59, 

62 
Intravenous Administration, 42 



102 



INDEX 



Intravenous vs. Intraspinous med- 
ication, 128 
Manufacture of, 19 
Needles, Care of, 154 
Other Derivatives of, 22 
Preparation for Intramuscular 

Use, 62 
Preparation of, 13 
Preparation of Solution of, 42 
Precursors of, 21 
Rapidity of Injection, 96 
Rectal Administration, 67 
Serological Effects of, 107 
Sodium Salt of, 21 
Technic of Administration, 42 
Temperature of Solution, 47 
Therapeutic Effects of, 31 
Therapeutic Efficiency, 32 
Use Following Acute Diseases, 31 
Use on Aged Persons, 31 
Variations in Different Brands of, 

19 
Asiphyl, n 
Atoxyl, 11, 21, 26 

B 
Blood Precipitates, 59 



Complement Fixation, 4 

Concentrated Neosalvarsan Injec- 
tion, 70 

Concentrated Salvarsan Injections, 
56 

Congenital Syphilis, 139 



Diabetes and Arsphenamine, 30 
Dietary for Syphilitic Patients, 156 
Dilute Neosalvarsan Injection, 72 
Distilling Apparatus, 45 
Distilled Water in Administration of 
Arsenicals, 44 



Early Meningitis, 116 

Effects of Arsphenamine and Mer- 
cury on Wassermann Reaction, 
106 

Embolism Following Arsphenamine, 
100 

Epifascial Neosalvarsan Injections, 
140 

F 

Filaria and Arsphenamine, 34 
Frambesia and Arsphenamine, 34 



Calomel-Neosalvarsan in Congenital 
Syphilis, 139 

Central Nervous System, Treat- 
ment of Syphilis of, 114 

Chancre, Excision of, 37 

Chemotherapy of Arsenic Com- 
pounds, 25 

Choroiditis and Salvarsan, 31 

"Cobble Stone" Buttocks, 80 

Cod Liver Oil in Syphilis, 86 

Collapse, Use of Tyramine in, 104 

Collapsules, 38, 81 

Colloidal Gold Test, 6 

Complement (Alexine), 1 



Galyl, 22 

Gold Curve, 117 

H 

Hectine, 11 

Hygiene for Syphilitic Patients, 155 



Infection of Physicians with Syphi- 
lis, i53 

Infiltration Following Arsphena- 
mine, 100 



INDEX 



163 



Intensive Salvarsan Treatment, 40, 

127, 131 
Interstitial Keratitis and Salvarsan, 

3i 
Iodides, 10, 82, 86, 142, 147, 148 

Effectiveness of Heavy Doses, 84 

In Tertiary and Latent Cases, 39 

Iodism, 84 

Methods of Employment, 82 
Iron in Syphilis, 86, 148 
Inunctions of Mercury, 78, 146 



Lange's Colloidal Gold Test, 6 
Luargol, 22 
Ludyl, 22 
Luetic Curve, 7 
Luetic Meningitis, 136 
Luetin Test, 144 

M 

Malaria and Arsphenamine, 34 
Marriage of the Syphilitic, 157 
Marsh Fever and Arsphenamine, 34 
Massage Following Mercury Injec- 
tion, 78 
Mercury, 10, 77, 106, 107, 112, 131, 
139, 142, 146, 149, 157 
Administration by Mouth, 79 
Administration, Technic of, 77 
Advantages and Disadvantages 

of Soluble Forms, 81 
Anatomical Sites for Inunctions, 

79 
Benzoate, 10, 134 
Bichlorid, 10, 38, 80, 85, 131, 146, 

147, 157 
Biniodid, 10, 147 
Blue Mass, 10 
Calomel, 10, 139, 146 
Collapsules, 38, 81 
Form to be Used, 80 
Fumigation, 79 



Gray Oil, 10, 80 

Inhalation, 79 

Intramuscular Injection, 77 

Intravenous Method, 80 

Inunctions, 78, 146 

Mercury with Chalk, 10, 146 

Not a Staple Curative Agent, 112 

Oleate, 10 

Protiodid, 10, 147 

Salicylate, 10, 38, 80, 86, 131, 134, 
149 

Serological Effects of, 107 

Succinimid, 10, 80 

Unguentum hydrargyri, 10, 78 
Methods of Preparing Intramuscu- 
lar Injections of Salvarsan 

Alt, 64 

American, 66 

British Army, 65 

Ehrlich, 62 

Michaelis, 64 

Oily Emulsions, 64 
Mixed Treatment, 147, 157 
Myocarditis and Arsphenamine, 30 

N 

Neoarsphenamine : 

Administration, Technic of, 69 
Apparatus for Injection, 73 
Concentrated Intravenous Admin- 
istration, 70 
Concentrated Method, Technic 

of, 73 

Dilute Intravenous Administra- 
tion, 69 

Dosage, 37, 85 

Evolution of, 20 

Gravity Method, 72 

Overconcentration, Dangers of, 72 

Preparation of Solution, 69 

Subcutaneous Method, Technic 
of, 74 

Time Necessary for Injection, 71 



164 



INDEX 



Nephritis and Arsphenamine, 30 

Neosalvarsan: 

Administration, Technic of, 69 
Apparatus for Injection, 73 
Comparative Use with Salvarsan, 

35 

Concentrated Intravenous Ad- 
ministration, 70 

Concentrated Method, Technic 

oi, 73 
Congenital Syphilis, 139 
Courses of Treatment, 87 
Dilute Intravenous Administra- 
tion, 69 
Dosage, 37, 85 

Epifascial Injections, 140, 146 
Gravity Method, 72 
Intra Arterial Injection in 

Cerebro-Spinal Syphilis, 135 
Jugular Vein, Injections in, 140, 

144 
Overconcentration, Dangers of, 72 
Preparation of Solutions, 69 
Sinus Longitudinalis, Injections 

in, 140 
Structural Formulas of, 28 
Subcutaneous Method, Technic 

of, 74 
Swift-Ellis Method, 114 
Time Necessary for Injection, 71 
Wide Field for in Congenital 
Syphilis, 145 
"914," 22 

Nitroglycerin in Arsphenamine Ad- 
ministration, 56 
Noguchi's Modification, 5 
Nux Vomica in Syphilis, 87 



Ogilvie's Modification, 119 
Optic Atrophy and Salvarsan, 125 
Organic Disease and Arsphenamine, 
3i 



Paralytica Dementia, 117 

Paresis, 136, 137 

Paretic Curve, 7 

Pentavalent Arsenic Compounds, 

25, 86, 142 
Persistent Positive Reaction and 

a Spirochetal Focus, 121 
Phlebitis following Arsphenamine, 

IOC 

Positive Results from Salvarsan and 

Mercury, 108 
Potassium Iodid, 10, 39, 83, 147, 148, 

iS7 

Potassium Permanganate in Malig- 
nant Syphilis, 148 

Potency of Trivalent Arsenic, 29 

Pregnant Women, Antiluetic Treat- 
ment of, 141 

Preparation of Patient for Sal- 
varsan, 52 

Pre-paresis, 125, 137 

Provocative Wassermanns, 39, 105 

Pyorrhea and Arsphenamine, 34 



Quinin in Malignant Syphilis, 148 

R 

Reactions and Accidents: 
Accidents, 100 
Atropin in, 88 
Causes of, 93 
Death, Causes of, 103 
Effects of disturbance of pul- 
monary circulation, 103 
Epinephrin in, 88, 134 
From Faulty Technic, 91 
Herxheimer Reaction, 92, 124 
Kidneys, Necessity of Watching, 

101 
Nerve Disturbances, 92 



INDEX 



*65 



Nitroid Crises, 88 
Revelations from Animal Experi- 
ments, IOI 
Some Late Reactions, 91 
Tyramine in Cases of Collapse, 
101 
Recurrent fever and Arsphenamine, 

34 
Reinfection, Syphilitic, 150 
Ricord's K. I. Formula, 83 



Salvarsan: 

Accidents Following Use of, 100 

Action on Spirochetae Pallidae, 39 

Advantages of in Congenital 
Syphilis, 143 

Alkalinization, Importance of, 46, 
50, 120 

And Mercury, 40. 

Apparatus for, 43 

Chemical Transformation of, 49 

Clinical Value of, 32 

Comparative Use with Neosal- 
varsan, 35 

Concentration of, 46, 56 

Contraindications, 30, 133 

Courses of Treatment, 86 

Danger of Too Concentrated 
Solution, 57, 96 

Dilution of, 47, 95 

Discovery of, 12 

Distilled Water for, 44 

Dosage of, 37, 85 

Effects on Wassermann Reaction, 
106 

Efficiency of, 32 

Filtering of Solution, 51 

History and Chemistry of, 11 

Indications for Use, 33 

Injection into Superior Longi- 
tudinal Sinus, 57 

In Luetic Meningitis, 136 



In Malignant Syphilis, 31, 148 
In Paresis, 136, 137 
In Pre-paresis, 125, 137 
Intensive Treatment, 40, 127, 131 
In Tabes, 31, 117, 136, 137 
In Tertiary Lesions of Viscera, 148 
Intracranial Method, 136 
Intramuscular Administration, 59, 

62 
Intraspinal Treatment, 120 
Ogilvie's Modification, 119 
Permeability of Meninges to Ar- 
senic, 137 
Pregnancy, Treatment during, 141 
Preparation of Solution, 42 
Rectal Administration, 67 
Serological Effects of, 107 
Sodium Hydroxide, Use of, 48 
Structural Formulas of, 28 
Subarachnoid Injections, 115 
Swift-Ellis Method, 114 
Technic of Administration, 42 
Temperature of Solution, 47 
Value of Large Production of, 19 

Septicemia and Neoarsphenamine, 3 5 

"606," 22 

Soamin, 26 

Sodium Cacodylate, 26 

Sodium Iodid, 10 

Spirarsyl, 22 

Spirochetae not Affected by Iodin, 82 

Strontium Iodid, 10 

Strychnin in Syphilis, 86 

Subcutaneous Injection of Neosal- 
varsan, 74 

Syphilitic Reinfection, 150 

Syphilis: 
Abortion of, 38 
Antenatal Treatment, 142 
Arsphenamine (Salvarsan), Treat- 
ment by, 42 
Central Nervous System, Treat- 
ment of Syphilis of, 1 14 
Congenital, 139 



i66 



INDEX 



Cure of, 150 

Dietary for Syphilitic Patients, 
1S6 

Dosage of Salvarsan and Neosal- 
varsan, 37 

Epifascial Neosalvarsan Injec- 
tions in Congenital Syphilis, 
139, 146 

Fordyce Technic, The, 123 

General Treatment, 86 

Hydrotherapeutic Treatment, 87 

Hygiene for Patients, 155 

Intensive Treatment, 40, 127, 131 

Intracranial Method of Treat- 
ment, 136 

Intraspinal Treatment, 120 

Iodides in Tertiary and Latent 
Cases, 39 

Malignant Syphilis, Treatment 
of, 148 

Mercurials and Iodides in, 77 

Necessity of Locating Focus of 
Infection, 123 

Necessity of Prompt Treatment, 

37 
Neoarsphenamine (Neosalvarsan), 

Treatment by, 69 
Neosalvarsan Intra-arterially in 

Cerebrospinal Lues, 135 
Plan of Treatment for, 37 
Pregnancy, Treatment during, 141 
Prevention of Infection, 153 
Provocative Wassermann in, 105 
Resume of Treatment, 85 
Salvarsan and Mercury Necessary 

in, 40 
Standard of Cure of, 152 
Subarachnoid Injections, 115 
Swift-Ellis Method, 114 
Syphilitic Aortitis, Endarteritis 

and Periarteritis, 148 
Tertiary Lesions of Viscera, 148 
Treatment of Long Standing 

Cases, 38 



Treatment of Primary and Sec- 
ondary Cases, 38 

Turkish Baths During Treat- 
ment, 87 

Visceral Syphilis, Treatment of, 
148 

Wassermann Reaction following 
Treatment, 39. 



Tabes Dorsalis, 117, 136, 137 
Technic of Salvarsan Injection, 42 
Thrombus following Arsphenamine, 

100 
Tick Fever and Arsphenamine, 34 
Trench Mouth and Arsphenamine, 

34 
Trivalent Arsenic Compounds, 28 
Tuberculosis and Arsphenamine, 30 
Tyramine in Cases of Collapse, 104 

U 

U. S. Public Health Service's In- 
structions on Arsenicals, 98 

Urine, Examination of, After In- 
jection, 31, 52 

V 

Vein, Choice of, 52 

Vincent's Angina and Arsphena- 
mine, 34 

Visceral Syphilis, Salvarsan in, 148 

Vision, Intraspinal Treatment in 
Preservation of, 124 

W 

Wassermann Reaction, 1 
After Salvarsan-Mercury Treat- 
ment, 39 
Clinical Application of, 8 
Effects of Arsphenamine and 
Mercury on, 106 



INDEX 167 

Indications for Provocative, 105 Provocative, 39, 105 

Negative Reactions, Significance Reaction in Latent Cases, 9 

of, 9 Value in Differential Diagnosis, 

Of Spinal Fluid, 39 8 

Positive Reactions, Significance Value in Standard of Cure, 152 

of, 8 When Can the Syphilitic Patient 

Positive Results from Salvarsan Marry? 157 

and Mercury, 108 



Printed in the United States of America 



